Methods of treating or preventing restless leg syndrome using sibutramine metabolites

ABSTRACT

Methods are disclosed for the treatment and prevention of disorders and conditions such as, but are not limited to: eating disorders; weight gain; obesity; irritable bowel syndrome; obsessive-compulsive disorders; platelet adhesion; apnea; affective disorders such as attention deficit disorders, depression, and anxiety; male and female sexual function disorders; restless leg syndrome; osteoarthritis; substance abuse including nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic neuropathy, and chronic pain; migraines; cerebral function disorders; chronic disorders such as premenstrual syndrome; and incontinence.  
     Pharmaceutical compositions and dosage forms are also disclosed which comprise a racemic or optically pure sibutramine metabolite and an optional additional pharmacologically active compound.

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 09/662,135, filed Sep. 14, 2000, which is acontinuation-in-part of U.S. application Ser. No. 09/372,158, filed Aug.11, 1999, both of which are incorporated herein by reference in theirentireties.

1. FIELD OF THE INVENTION

[0002] The invention relates to methods of using and compositionscomprising dopamine reuptake inhibitors such as racemic and opticallypure metabolites of sibutramine, optionally in combination with otherpharmacologically active compounds.

2. BACKGROUND OF THE INVENTION

[0003] Sibutramine, chemically named[N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine, isa neuronal monoamine reuptake inhibitor which was originally disclosedin U.S. Pat. Nos. 4,746,680 and 4,806,570. Sibutramine inhibits thereuptake of norepinephrine and, to a lesser extent, serotonin anddopamine. See, e.g., Buckett et al., Prog. Neuro-psychopharm. & Biol.Psychiat., 12:575-584, 1988; King et al., J. Clin. Pharm., 26:607-611(1989).

[0004] Racemic sibutramine is sold as a hydrochloride monohydrate underthe tradename MERIDIA®, and is indicated for the treatment of obesity.Physician's Desk Reference® 1494-1498 (53^(rd) ed., 1999). The treatmentof obesity using racemic sibutramine is disclosed, for example, in U.S.Pat. No. 5,436,272.

[0005] Sibutramine appears to have been extensively studied, andreportedly could be used in the treatment of a variety of disorders. Forexample, U.S. Pat. Nos. 4,552,828, 4,746,680, 4,806,570, and 4,929,629disclose methods of treating depression using racemic sibutramine, andU.S. Pat. Nos. 4,871,774 and 4,939,175 disclose methods of treatingParkinson's disease and senile dementia, respectively, using racemicsibutramine. Other uses of sibutramine are disclosed by PCT publicationsWO 95/20949, WO 95/21615, WO 98/11884, and WO 98/13033. Further, theoptically pure entantiomers of sibutramine have been considered fordevelopment. For example, PCT publications WO 94/00047 and 94/00114disclose methods of treating depression and related disorders using theR- and (S)-entantiomers of sibutramine, respectively.

[0006] Sibutramine is rapidly absorbed from the gastrointestinal tractfollowing oral administration and undergoes an extensive first-passmetabolism that yields the primary metabolites, desmethylsibutramine anddidesmethylsibutramine, shown below.

[0007] It has been reported that desmethylsibutramine anddidesmethylsibutramine are more potent in vitro noradrenaline and5-hydroxytryptamine (5HT; serotonin) reuptake inhibitors thansibutramine. Stock, M. J., Int'l J. Obesity, 21(Supp. 1):S25-S29 (1997).It has further been reported, however, that sibutramine and itsmetabolites have negligible affinities for a wide range ofneurotransmitter receptors, including serotonergic (5-HT₁, 5-HT₁,5-HT_(1A), 5-HT_(2A), 5-HT_(2C), adrenergic, dopaminergic, muscarinic,histaminergic, glutamate, and benzodiazepine receptors. Id.

[0008] Sibutramine has a variety of adverse effects. See, e.g.,Physician's Desk Reference® 1494-1498 (53^(rd) ed., 1999). Coupled withthe reported benefits and therapeutic insufficiencies of sibutramine,this fact has encouraged the discovery of compounds and compositionsthat can be used in the treatment or prevention of disorders such as,but not limited to, sexual (e.g., erectile) dysfunction, affectivedisorders, weight gain or obesity, cerebral function disorders, pain,obsessive compulsive disorder, substance abuse, chronic disorders,anxiety, eating disorders, migraines, and incontinence. In particular,compounds and compositions are desired that can be used for thetreatment and prevention of such disorders and conditions whileincurring fewer of the adverse effects associated with sibutramine.

3. SUMMARY OF THE INVENTION

[0009] This invention encompasses methods of treating and preventingdisorders and conditions that are ameliorated by the inhibition ofneuronal monoamine uptake, which comprise administering to a patient inneed of such treatment or prevention a therapeutically orprophylactically effective amount of a neuronal monoamine reuptakeinhibitor. Preferred neuronal monoamine reuptake inhibitors aresibutramine metabolites. In specific methods of the invention, theneuronal monoamine reuptake inhibitor is optionally administered incombination with an additional pharmacologically active compound.

[0010] Examples of disorders and conditions that are ameliorated by theinhibition of neuronal monoamine uptake include, but are not limited to:eating disorders; weight gain; obesity; irritable bowel syndrome;obsessive-compulsive disorders; platelet adhesion; apnea; affectivedisorders such as attention deficit disorders, depression, and anxiety;male and female sexual function disorders; restless leg syndrome;osteoarthritis; substance abuse including nicotine and cocaineaddiction; narcolepsy; pain such as neuropathic pain, diabeticneuropathy, and chronic pain; migraines; cerebral function disorders;chronic disorders such as premenstrual syndrome; and incontinence.

[0011] This invention further encompasses pharmaceutical compositionsand dosage forms which can be used, for example, in the methodsdisclosed herein. Preferred pharmaceutical compositions of the inventioncomprise a therapeutically or prophylactically effective amount of asibutramine metabolite and optionally an additional pharmacologicallyactive compound.

[0012] 3.1. Definitions

[0013] As used herein, the term “prodrug” means a derivative of acompound that can hydrolyze, oxidize, or otherwise react underbiological conditions (in vitro or in vivo) to provide the compound.Examples of prodrugs include, but are not limited to, derivatives ofdesmethylsibutramine and didesmethylsibutramine that comprisebiohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphates. As used herein,prodrugs of didesmethylsibutramine do not include desmethylsibutramineand sibutramine, and prodrugs of desmethylsibutramine do not includesibutramine.

[0014] As used herein, the terms “biohydrolyzable carbamate,”“biohydrolyzable carbamate,” “biohydrolzyable ureide,” “biohydrolyzablephosphate” mean a carbonate, ureide, or phosphate, respectively, of acompound that either: 1) does not interfere with the biological activityof the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically inactive but is converted in vivo to thebiologically active compound.

[0015] Examples of biohydrolyzable carbamates include, but are notlimited to, lower alkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

[0016] As used herein, the term “biohydrolyzable ester” means an esterof a compound that either: 1) does not interfere with the biologicalactivity of the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically inactive but is converted in vivo to thebiologically active compound. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters.

[0017] As used herein, the term “biohydrolyzable amide” means an amideof a compound that either: 1) does not interfere with the biologicalactivity of the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically inactive but is converted in vivo to thebiologically active compound. Examples of biohydrolyzable amidesinclude, but are not limited to, lower alkyl amides, α-amino acidamides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

[0018] As used herein, the term “biohydrolyzable ureide” means a ureideof a compound that either: 1) does not interfere with the biologicalactivity of the compound but can confer upon that compound advantageousproperties in vivo, such as uptake, duration of action, or onset ofaction; or 2) is biologically inactive but is converted in vivo to thebiologically active compound.

[0019] As used herein, the term “biohydrolyzable phosphate” means aphosphate of a compound that either: 1) does not interfere with thebiological activity of the compound but can confer upon that compoundadvantageous properties in vivo, such as uptake, duration of action, oronset of action; or 2) is biologically inactive but is converted in vivoto the biologically active compound.

[0020] As used herein, the term “pharmaceutically acceptable salt”refers to a salt prepared from a pharmaceutically acceptable non-toxicinorganic or organic acid. Inorganic acids include, but are not limitedto, hydrochloric, hydrobromic, hydrojodic, nitric, sulfuric, andphosphoric. Organic acids include, but are not limited to, aliphatic,aromatic, carboxylic, and sulfonic organic acids including, but notlimited to, formic, acetic, propionic, succinic, benzoiccamphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic,mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic,furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,pantothenic, benzenesulfonic, stearic, sulfanilic, alginic, andgalacturonic acid.

[0021] As used herein, a composition that is “substantially free” of acompound means that the composition contains less than about 20% byweight, more preferably less than about 10% by weight, even morepreferably less than about 5% by weight, and most preferably less thanabout 3% by weight of the compound.

[0022] As used herein, the terms “optically pure,” “enantiomericallypure,” “pure enantiomer,” and “optically pure enantiomer” mean acomposition that comprises one enantiomer of a compound and issubstantially free of the opposite enantiomer of the compound. A typicaloptically pure compound comprises greater than about 80% by weight ofone enantiomer of the compound and less than about 20% by weight of theopposite enantiomer of the compound, more preferably greater than about90% by weight of one enantiomer of the compound and less than about 10%by weight of the opposite enantiomer of the compound, even morepreferably greater than about 95% by weight of one enantiomer of thecompound and less than about 5% by weight of the opposite enantiomer ofthe compound, and most preferably greater than about 97% by weight ofone enantiomer of the compound and less than about 3% by weight of theopposite enantiomer of the compound. For example, optically pure (R)sibutramine comprises at least about 80% by weight (t) sibutramine andless than about 20% by weight (S) sibutramine.

[0023] As used herein, the term “neuronal monoamine reuptake inhibitor”means a substance that inhibits the reuptake of neuronal monoamines suchas dopamine, serotonin, and norepinephrine as determined using in vitroassays known to those skilled in the art. Preferred neuronal monoaminereuptake inhibitors are dopamine reuptake inhibitors, and sibutraminemetabolites in particular. More preferred neuronal monoamine reuptakeinhibitors are optically pure sibutramine metabolites.

[0024] As used herein, the term “dopamine reuptake inhibitor” means asubstance that inhibits the reuptake of dopamine as determined using invitro assays know to those skilled in the art. Preferred dopaminereuptake inhibitors are sibutramine metabolites and apomorphine.

[0025] As used herein, the term “sibutramine metabolite” encompasses,but is not limited to, racemic and optically pure desmethylsibutramineand didesmethylsibutramine, i.e., (R)-desmethylsibutramine,(S)-desmethylsibutramine, (R/S)-desmethylsibutramine,(R)-didesmethylsibutramine, (S)-didesmethylsibutramine, and(R/S)-didesmethylsibutramine. Preferred sibutramine metabolites areoptically pure.

[0026] It should further be noted that names used herein to identifycompounds of the invention may differ from those that are concordantwith International Union of Pure and Applied Chemistry (IUPAC) namingconventions. If there is a discrepancy between a structure depictedherein and a name given that structure, the depicted structure is to beaccorded more weight. In addition, if the stereochemistry of a structureor a portion of a structure is not indicated with, for example, bold ordashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of it.

4. DETAILED DESCRIPTION OF THE INVENTION

[0027] This invention relates, in part, to methods of treating andpreventing disorders and conditions in patients (e.g., mammals such ashumans, dogs, cats, and feedstock) that are ameliorated by theinhibition of the reuptake of neuronal monoamines (e.g., dopamine,serotonin, and norepinephrine). The invention further relates topharmaceutical compositions and dosage forms that can be used in suchmethods.

[0028] Specific disorder and conditions that are ameliorated by theinhibition of neuronal monoamine uptake include, but-are not limited to:eating disorders such as weight gain and obesity; platelet adhesion;apnea; obsessive-compulsive disorders; affective disorders (e.g., ADHD),depression, or anxiety, male and female sexual function disorders, suchas erectile dysfunction; restless leg syndrome; osteoarthritis;irritable bowel syndrome; substance abuse including, nicotine addictionfrom cigarette smoking or chewing tobacco, and cocaine addiction;migraines; chronic pain; pain, such as neuropathic pain, such asdiabetic neuropathy; cerebral function disorders; chronic disorders; andincontinence.

[0029] Methods of the invention comprise administering to a patient inneed of treatment or prevention a therapeutically or prophylacticallyeffective amount of neuronal monoamine reuptake inhibitor. Preferredneuronal monoamine reuptake inhibitors are dopamine reuptake inhibitors,such as sibutramine metabolites and pharmaceutically acceptable salts,solvates, clathrates, and prodrugs thereof. Preferred sibutraminemetabolites are optically pure. Specific preferred sibutraminemetabolites are (R)-desmethylsibutramine and (R)-didesmethylsibutramine.Another preferred dopamine reuptake inhibitor is apomorphine.

[0030] A first embodiment of the invention encompasses a method oftreating or preventing a sexual function disorder in a patient in needof such treatment or prevention, which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a dopamine reuptake inhibitor,optionally in combination with a 5-HT₃ antagonist. In one method of thisembodiment, a sibutramine metabolite is administered in combination witha 5-HT₃ antagonist. In another method of this embodiment, apomorphine isadministered in combination with a 5-HT₃ antagonist.

[0031] In a preferred method of this embodiment, a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, is administered to a patient orally,transdermally, or mucosally.

[0032] In another preferred method of this embodiment, the patient inneed of treatment or prevention is elderly or postmenstrual.

[0033] As used herein, the terms “sexual dysfunction” and “sexualfunction disorder”encompass sexual dysfunction in men and women causedby psychological and/or physiological factors. Examples of sexualdysfunction include, but are not limited to, erectile dysfunction,vaginal dryness, lack of sexual excitement, or inability to obtainorgasm. The term “sexual dysfunction” further encompasses psycho-sexualdysfunction Examples of psychosexual dysfunction include, but are notlimited to, inhibited sexual desire, inhibited sexual excitement,inhibited female orgasm, inhibited male orgasm, premature ejaculation,functional dyspareunia, functional vaginisms, and atypical psychosexualdysfunction.

[0034] Another embodiment of the invention encompasses a method oftreating or preventing an affective disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof.

[0035] Affective disorders include, but are not limited to, depression(e.g., melancholia), attention deficit disorder (including attentiondeficit disorder with hyperactivity and attention deficit/hyperactivitydisorder), bipolar and manic conditions, dysthymic disorder, andcyclothymic disorder. As used herein, the terms “attention deficitdisorder” (ADD), “attention deficit disorder with hyperactivity” (ADDH),and “attention deficit/hyperactivity disorder” (AD/HD), are used inaccordance with their accepted meanings in the art. See, e.g.,Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed.,American Psychiatric Association, 1997 (DSM-IV™) and Diagnostic andStatistical Manual of Mental Disorders, 3^(d) Ed., American PsychiatricAssociation (1981) (DSM-III™).

[0036] A preferred method of this embodiment is a method of treating orpreventing attention deficit disorder which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof. In a particular embodiment, the method can also be usedto treat or prevent a condition in children (e.g., ages 3-18).

[0037] Another preferred method of this embodiment is a method oftreating or preventing depression which comprises administering to apatient in need of such treatment or prevention a therapeutically orprophylactically effective amount of a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof.

[0038] As used herein, the term “treating or preventing depression”means relief from or prevention of the symptoms of depression whichinclude, but are not limited to, changes in mood, feelings of intensesadness, despair, mental slowing, loss of concentration, pessimisticworry, agitation, and self-deprecation. Physical changes can also berelieved or prevented by this method, and include, but are not limitedto, insomnia, anorexia, decreased energy and libido, and abnormalhormonal circadian rhythms.

[0039] Another embodiment of the invention encompasses a method oftreating or preventing weight gain or obesity which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, optionally in combination with a lipaseinhibitor.

[0040] As used herein, the term “treating or preventing weight gain orobesity” means reduction of weight, relief from being overweight,treating weight gain caused by the administration of other drugs, relieffrom gaining weight, or relief from obesity, and prevention from gainingweight, all of which are usually due to unnecessary consumption of food.The invention also encompasses methods of treating or preventingconditions incidental to obesity including, but not limited to,hypertension, such as pulmonary hypertension; cancers, such as breast,colon, gall bladder, and endometrial; gall stones; cardiovasculardisease, such as dyslipidemia and carotid intimal medial thickening;hiatial hernia; osteoarthritis; gout; thyroid disease, such as diabetes;gastro-esophogeal reflux disease; menstrual dysfunction; andinfertility.

[0041] Another embodiment encompasses a method of treating or preventinga disorder associated with the administration of a lipase inhibitor forobesity or weight management, such as, for example, orlistat (XENICAL®),which comprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of asibutramine metabolite, or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, or prodrug thereof. As used herein, the term“treating or preventing a disorder associated with the administration ofa lipase inhibitor” means alleviating or reducing adverse effectsassociated with administration of a lipase inhibitor, which include, butare not limited to, infectious diarrhea, oily fecal spotting, flatuswith discharge, fecal urgency, fatty/oily stool, oily evacuation,increased defecation, anal leakage, and fecal incontinence.

[0042] Another embodiment encompasses a method of treating or preventinga cerebral function disorder which comprises administering to a patientin need of such treatment or prevention a therapeutically orprophylactically effective amount of a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, or clathratethereof.

[0043] Cerebral function disorders include, but are not limited to,senile dementia, Alzheimer's type dementia, memory loss,amnesia/amnestic syndrome, disturbance of consciousness, coma, loweringof attention, speech disorders, Parkinson's disease, Lennox syndrome,autism, epilepsy, hyperkinetic syndrome, and schizophrenia Cerebralfunction disorders can be induced by factors including, but not limitedto, cerebrovascular diseases, such as cerebral infarction, cerebralbleeding, cerebral arteriosclerosis, cerebral venous thrombosis, andhead injuries, and conditions having symptoms selected from the groupconsisting of disturbances of consciousness, senile dementia, coma,lowering of attention, and speech disorders. As-used herein, the term“treating or preventing a cerebral function disorder” means relief fromor prevention of one or more symptoms associated with cerebral functiondisorders.

[0044] Another embodiment encompasses a method of treating or preventingrestless leg syndrome, which comprises administering to a patient inneed of such treatment or prevention a therapeutically orprophylactically effective amount of a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof. In a preferred embodiment, the patient is at leastabout 50, 60, or 70 years of age. In another preferred method of thisembodiment, the sibutramine metabolite is administered in combinationwith at least one of pergolide, carbidopa, levodopa, oxycodone,carbamazepine, gabapentin, or pharmaceutically acceptable salts,solvates, hydrates, clathrates, prodrugs, optically andpharmacologically active stereoisomers, or pharmacologically activemetabolites thereof.

[0045] As used herein, the term “restless leg syndrome” encompasses adisorder that typically occurs during sleep or rest, or just beforesleep or rest, and which is characterized by uncomfortable sensations inthe legs. The disorder often occurs in patients older than about 50years of age. Examples of uncomfortable sensations in the legs include,but are not limited to, pulling, drawing, crawling, wormy, boring,tingling, pins and needles, prickly and sometimes painful sensationsthat are usually accompanied by an overwhelming urge to move the legs.As used herein, the term “restless leg syndrome” also encompasses EkbomSyndrome, Wittmaack-Ecbom Syndrome, Hereditary Acromelalgia, andAnxieties Tibialis.

[0046] Another embodiment encompasses a method of treating or preventingpain which comprises administering to a patient in need of suchtreatment or prevention a therapeutically or prophylactically effectiveamount of a sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof. In a particularembodiment, the pain is chronic pain, such as neuropathic pain anddiabetic neuropathy.

[0047] Still another embodiment of the invention encompasses a method oftreating or preventing obsessive-compulsive disorder which comprisesadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof.

[0048] As used herein, the terms “obsessive-compulsive disorder,”“pre-menstrual syndrome, ” “anxiety,” and “eating disorder” are usedconsistently with their accepted meanings in the art. See, e.g., DSM-IV™and DSM-III™. The term “methods of treating or preventing” when used inconnection with these disorders means the amelioration, prevention, orrelief from symptoms and/or effects associated with these disordersAnother embodiment encompasses a method of treating or preventingsubstance abuse which comprises administering to a patient in need ofsuch treatment or prevention a therapeutically or prophylacticallyeffective amount of a sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof. In aparticular embodiment, the substance abuse is cocaine addiction oralcohol addiction.

[0049] As used herein, the term “substance abuse” encompasses the abuseof, and physical and/or psychological addiction to, drugs or alcohol.The term “substance abuse” further encompasses its accepted meaning inthe art. See, e.g. DSM-IV™ and DSM-III™. A preferred method encompassedby this embodiment is a method of treating or preventing cocaine and/orheroin abuse.

[0050] Another embodiment encompasses a method of treating or preventingnicotine addiction which comprises administering to a patient in need ofsuch treatment or prevention a therapeutically or prophylacticallyeffective amount of a sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof.Nicotine addiction includes nicotine addiction of all known forms, suchas addiction to cigarettes, cigars and/or pipes, and chewing tobacco.

[0051] Another embodiment encompasses a method of eliciting smokingcessation which comprises administering to a patient who smokes tobaccoa therapeutically effective amount of a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof. In a preferred method encompassed by this embodiment,the sibutramine metabolite, or pharmaceutically acceptable salt,solvate, hydrate, clathrate, or prodrug thereof is administered orally,mucosally, or transdermally. In a more preferred method, the sibutraminemetabolite or pharmaceutically acceptable salt, solvate, hydrate, orclathrate thereof is administered transdermally.

[0052] In another preferred method of this embodiment, the sibutraminemetabolite or pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, is administered in combination with atherapeutically or prophylactically effective amount of nicotine.Preferably, the nicotine and/or sibutramine metabolite orpharmaceutically acceptable salt, solvate, hydrate clathrate, or prodrugthereof is administered orally, mucosally, or transdermally. Morepreferably, the nicotine and/or sibutramine metabolite orpharmaceutically acceptable salt, solvate, ester, clathrate, or prodrugthereof is administered transdermally.

[0053] Another method encompassed by this embodiment is a method oftreating or preventing weight gain associated with smoking cessationwhich comprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of asibutramine metabolite, or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, or prodrug thereof.

[0054] Another embodiment encompasses a method of treating or preventingweight gain associated with the administration of other drugs that mayinduce weight gain, which comprises administering to a patient in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, ester, clathrate, or prodrug thereof.

[0055] Another embodiment encompasses a method of treating or preventinga chronic disorder including, but not limited to, narcolepsy, chronicfatigue syndrome, seasonal affective disorder, fibromyalgia, andpremenstrual syndrome (or premenstrual dysphoric disorder), whichcomprises administering to a patient in need of such treatment orprevention a therapeutically or prophylactically effective amount of asibutramine metabolite, or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, or prodrug thereof. Preferred methods are methods oftreating or preventing narcolepsy, premenstrual syndrome, or chronicfatigue syndrome.

[0056] Another embodiment encompasses a method of treating or preventinganxiety which comprises administering to a patient in need of suchtreatment or prevention a therapeutically or prophylactically effectiveamount of a sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof.

[0057] Another embodiment encompasses a method of treating or preventingan eating disorder including, but not limited to, anorexia, bulimia,binging, and snacking, which comprises administering to a patient inneed of such treatment or prevention a therapeutically orprophylactically effective amount of a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof.

[0058] Another embodiment encompasses a method of treating or preventingmigraines which comprises administering to a patient in need of suchtreatment or prevention a therapeutically or prophylactically effectiveamount of a sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof.

[0059] Another embodiment encompasses a method of treating or preventingincontinence with comprises administering to a patient in need of suchtreatment or prevention a therapeutically or prophylactically effectiveamount of a sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, ester, clathrate, or prodrug thereof. In particular, thesibutramine metabolite can be used to treat fecal incontinence, stressurinary incontinence (“SUI”), urinary exertional incontinence, urgeincontinence, reflex incontinence, passive incontinence, anal leakage,and overflow incontinence.

[0060] As used herein, the term “treating or preventing incontinence”means treatment, prevention of, or relief from the symptoms ofincontinence including involuntary voiding of feces or urine, anddribbling or leakage or feces or urine, which may be due to one or morecauses including, but not limited to, pathology altering sphinctercontrol, loss of cognitive function, overdistention of the bladder,hyper-reflexia and/or involuntary urethral relaxation, weakness of themuscles associated with the bladder or neurologic abnormalities.

[0061] A preferred method encompassed by this embodiment is a method oftreating or preventing stress urinary incontinence. In a furtherpreferred method encompassed by this embodiment, the patient is an elderhuman of an age greater than about 50 or a child of an age less thanabout 13.

[0062] In a specific embodiment of each of the methods of treatment orprevention of the invention, a therapeutically or prophylacticallyeffective amount of a racemic or optically pure sibutramine metaboliteis administered to a patient in combination with an additionalpharmacologically active compound. Examples of additionalpharmacologically active compounds include, but are not limited to,drugs that act on the central nervous system (“CNS”), such as, but notlimited to: 5-HT (e.g., 5-HT₃ and 5-HT_(1A)) agonists and antagonists;selective serotonin reuptake inhibitors (“SSRIs”); hypnotics andsedatives; drugs useful in treating psychiatric disorders includingantipsychotic and neuroleptic drugs, antianxiety drugs, antidepressants,and mood-stabilizers; CNS stimulants such as amphetamines; dopaminereceptor agonists; antimonic agents; antipanic agents; cardiovascularagents (e.g., beta blockers and angiotensin converting enzymeinhibitors); phosphodiesterase inhibitors; antivirals; antibiotics;antifingals; and antineoplastics. As discussed in more detail herein,the particular additional pharmacologically active compound used in amethod will depend upon the disease or condition being treated orprevented, as well as the particular patient being treated.

[0063] The invention also encompasses pharmaceutical compositions andsingle unit dosage forms that can be used, for example, in the methodsdescribed herein. One embodiment of the invention encompasses apharmaceutical composition or dosage form that comprises a sibutraminemetabolite, preferably an optically pure sibutramine metabolite.Particular pharmaceutical compositions and single unit dosage forms ofthe invention comprise a sibutramine metabolite and an additionalpharmacologically active compound.

[0064] 4.1. Synthesis of Sibutramine Metabolites

[0065] Racemic sibutramine, desmethylsibutramine, anddidesmethylsibutramine can be prepared by methods known to those ofordinary skill in the art. See, e.g. U.S. Pat. No. 4,806,570, which isincorporated herein by reference; J. Med. Chem., 2540 (1993) (tosylationand azide replacement); Butler, D., J. Org. Chem., 36:1308 (1971)(cycloalkylation in DMSO); Tetrahedron Left., 155-58 (1980) (Grignardaddition to nitrile in benzene); Tetrahedron Lett., 857 (1997) (OH toazide); and Jeffery, J. E., et al., J. Chem. Soc. Perkin. Trans 1, 2583(1997). A preferred method of preparing racemic sibutramine is providedbelow in Example 1.

[0066] Racemic sibutramine, desmethylsibutramine, anddidesmethylsibutramine can be prepared from each other, as can opticallypure forms of the compounds. Preferred methods of preparing compoundsfrom one another are provided below in Examples 2, 3, and 8. Opticallypure enantiomers of sibutramine and its metabolites can be preparedusing techniques known in the art A preferred technique is resolution byfractional crystallization of diastereomeric salts formed with opticallyactive resolving agents. See, e.g., “Enantiomers, Racemates andResolutions,” by J. Jacques, A. Collet, and S. H. Wilen,(Wiley-Interscience, New York, 1981); S. H. Wilen, A. Collet, and J.Jacques, Tetrahedron, 2725 (1977); E. L. Eliel Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and S. H. Wilen Tables of ResolvingAgents and Optical Resolutions 268 (E. L. Eliel ed., Univ. of Notre DamePress, Notre Dame, Ind., 1972).

[0067] Because sibutramine, desmethylsibutramine, anddidesmethylsibutramine are basic amines, diastereomeric salts of thesecompounds that are suitable for separation by fractional crystallizationare readily formed by addition of optically pure chiral acid resolvingagents. Suitable resolving agents include, but are not limited to,optically pure tartaric, camphorsulfonic acid, mandelic acid, andderivatives thereof. Optically pure isomers of sibutramine,desmethylsibutramine, and didesmethylsibutramine can be recovered eitherfrom the crystallized diastereomer or from the mother liquor, dependingon the solubility properties of the particular acid resolving agentemployed and the particular acid enantiomer used. The identity andoptical purity of the particular sibutramine or sibutramine metaboliteisomer so recovered can be determined by polarimetry or other analyticalmethods.

[0068] Racemic and optically pure sibutramine metabolites are preferablysynthesized directly by methods such as those disclosed by Jeffery, J.E., et al., J. Chem. Soc. Perkin. Trans 1, 2583 (1996). A preferredmethod of directly synthesizing racemic desmethylsibutramine comprisesthe reduction of cyclobutanecatbonitrile (CCBC) to form an aldehydeintermediate which is subsequently reacted with an amine such as, butnot limited to, methylamine. This method is applied below in Example 4.

[0069] Another preferred method of directly synthesizing racemicdesmethylsibutramine comprises the reaction of CCBC with a compound offormula i-BuMX, wherein X is Br or I and M is selected from the groupconsisting of Li, Mg, Zn, Cr, and Mn. Preferably, the compound is of theformula i-BuMgBr. This reaction produces a product which is subsequentlyreduced, converted to an intermediate comprising an aldehyde bound tothe nitrogen atom, which intermediate is finally converted todesmethylsibutramine in a step that comprises the addition of a lewisacid. Preferred lewis acids are selected from the group consisting ofBH₃-THF, BF₃-THF, La(O-i-Pr)₃, Zr(O-i-Pr)₄, Ti(O-i-Pr)₂Cl₂, SnCl₄, andMgBr₂-OEt₂. A most preferred lewis acid is BH₃-THF. This method isapplied below in Example 5.

[0070] The enantiomers of desmethylsibutramine can be resolved by theformation of chiral salts as described above. Preferred chiral acidsused to form the chiral salts include, but are not limited to, tartaricand mandelic acids. If tartaric acid is used, preferred solvent systemsinclude, but are not limited to, ethanol/water and isopropylalcohol/water. If mandelic acid is used, a preferred solvent system isethyl acetate/hexane. The resolution of desmethylsibutramine is shownbelow in Examples 6 and 7.

[0071] A preferred method of directly synthesizing racemicdidesmethylsibutramine comprises the reaction of CCBC with a compound offormula i-BuMX, wherein X is Br or I and M is selected from the groupconsisting of Li, Mg, Zn; Cr, and Mn. Preferably, the compound is of theformula i-BuMgBr. The product of this reaction is then reduced undersuitable reaction conditions. Application of this method is shown belowin Example 9.

[0072] The enantiomers of didesmethylsibutramine can be resolved by theformation of chiral salts, as described above. Preferred chiral acidsused to form the chiral salts include, but are not limited to, tartaricacid. Preferred solvent systems include, but are not limited to,acetonitrile/water/methanol and acetonitrile/methanol. The resolution ofdidesmethylsibutramine is shown below in Examples 11 and 12.

[0073] 4.2. Methods of Treatment and Prevention

[0074] In each of the methods of the invention, a therapeutically orprophylactically effective amount of a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, is administered to a patient. Preferred sibutraminemetabolites are optically pure.

[0075] In specific methods of the invention, the sibutramine metabolite,or pharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, is administered to a patient in an amount from about0.1 mg to about 60 mg, preferably from about 2 mg to about 30 mg, andmore preferably from about 5 mg to about 15 mg. Such amounts can beadministered daily as needed for the treatment of acute and chronicdiseases and conditions.

[0076] Optionally, the sibutramine metabolite is adjunctivelyadministered (i.e., administered in combination) with one or moreadditional pharmacologically active compounds. In other words, asibutramine metabolite and an additional pharmacologically activecompound can be administered to a patient as a combination, concurrentlybut separately, or sequentially by any suitable route. Suitable routesof administration include oral, mucosal (e.g., nasal, sublingual,buccal, rectal, and vaginal), parenteral (e.g., intravenous,intramuscular or subcutaneous), and transdermal routes.

[0077] As physicians and those skilled in the art of pharmacology willreadily appreciate, the particular additional pharmacologically activecompounds that can be administered in combination with a sibutraminemetabolite will depend on the particular disease or condition beingtreated or prevented, and may also depend on the age and health of thepatient to which the compounds are to be administered.

[0078] Additional pharmacologically active compounds that can be used inthe methods and compositions of the invention include, but are notlimited to, drugs that act on the central nervous system (“CNS”), suchas, but not limited to: 5-HT (e.g., 5-HT₁ and 5-HT_(1A)) agonists andantagonists; selective serotonim reuptake inhibitors (“SSRIs”);hypnotics and sedatives; drugs useful in treating psychiatric disordersincluding antipsychotic and neuroleptic drugs, antianxiety drugs,antidepressants, and mood-stablizers; CNS stimulants such asamphetamines; dopamine receptor agonists; antimonic agents; antipanicagents; cardiovascular agents (e.g., beta blockers and angiotensinconverting enzyme inhibitors); phosphodiesterase inhibitors; antivirals;antibiotics; antifungals; and antineoplastics.

[0079] More specific drugs that act on the CNS include, but are notlimited to, SSRIs, benzodiazepine compounds, tricyclic antidepressants,antipsychotic agents, anti-anxiolytic agents, 6-adrenergic antagonists,5-HT_(1A) receptor antagonists, and 5-HT₃ receptor agonists. Even morespecific drugs that act on the CNS include, but are not limited to,lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine,and valium.

[0080] Examples of 5-HT₃ antagonists that can be used in compositionsand methods of the invention include, but are not limited to,granisetron (KYTRIL®), metoclopramide (REGLAN®), ondansetron (ZOFRAN®),renzapride, zacopride, tropisetron, and optically active stereoisomers,active metabolites, and pharmaceutically acceptable salts, solvates,hydrates, clathrates, prodrugs, optically and pharmacologically activestereoisomers, and pharmacologically active metabolites thereof.Preferred 5-HT₃ antagonists are antiemetic agents.

[0081] Selective serotonin reuptake inhibitors are compounds thatinhibit the central nervous system uptake of serotonin while havingreduced or limited affinity for other neurologically active receptors.Examples of SSRIs include, but are not limited to, citalopram (CELEXA®);fluoxetine (PROZAC®) fluvoxamine (LUVOX®); paroxetine (PAXIL®);sertraline (ZOLOFT®); venlafaxine (EFFEXOR®); and pharmaceuticallyacceptable salts, solvates, hydrates, clathrates, prodrugs, opticallyand pharmacologically active stereoisomers, and pharmacologically activemetabolites thereof.

[0082] Disorders that can be treated or prevented using a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, in combination with an SSRIs include, butare not limited to, depression, affective disorders, anxiety, eatingdisorders, and cerebral function disorders such as those describedherein.

[0083] Benzodiazepine compounds that can be used in the methods andcompositions of the invention include, but are not limited to, thosedescribed in Goodman & Gilman, The Pharmacological Basis ofTherapeutics, 362-373 (9^(th) ed. McGraw-Hill, 1996). Examples ofspecific benzodiazpines include, but are not limited to, alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, triazolam, pharmacologically active metabolites andstereoisomers thereof, and pharmaceutically acceptable salts, solvates,hydrates, esters, clathrates, and prodrugs thereof. The tradenames ofsome of these compounds are provided below.

[0084] The clinician, physician, or psychiatrist will appreciate whichof the above compounds can be used in combination with a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, for the treatment or prevention of agiven disorder, although preferred combinations are disclosed herein.

[0085] Disorders that can be treated or prevented using a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, in combination with a benzodiazepine suchas those listed above include, but are not limited to, depression,affective disorders, anxiety, eating disorders, and cerebral functiondisorders such as those described herein.

[0086] The invention further encompasses methods of using andpharmaceutical compositions comprising sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, in combination with an antipsychotic agent.Antipsychotic agents are used primarily in the management of patientswith psychotic or other serious psychiatric illness marked by agitationand impaired reasoning. These drugs have other properties that possiblyare useful clinically, including antiemetic and antihistamine effectsand the ability to potentiate analgesics, sedatives, and generalanesthetics. Specific antipsychotic drugs are tricyclic antipsychoticdrugs, of which there are three subtypes: phenothiazines, thioxanthenes,and other heterocyclic compounds, all of which can be used in themethods and compositions of the invention. See, e.g., Goodman & Gilman,The Pharmacological Basis of Therapeutics, 404 (9^(th) ed. McGraw-Hill,1996).

[0087] Specific tricyclic antipsychotic compounds include, but are notlimited to, chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chlorprothixene,thiothixene, clozapine, haloperidol, loxapine, molindone, pimozide,risperidone, desipramine, and pharmaceutically acceptable salts,solvates, hydrates, clathrates, prodrugs, optically andpharmacologically active stereoisomers, and pharmacologically activemetabolites thereof. The tradenames of some of these compounds areprovided herein.

[0088] Disorders that can be treated or prevented using a sibutraminemetabolite, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, in combination with an antipsychoticcompound, and particularly a tricyclic antipsychotic compound, include,but are not limited to, affective disorders (e.g., depression), anxiety,eating disorders, and cerebral function disorders (e.g., schizophrenia)such as those described herein.

[0089] The invention further encompasses methods of using andpharmaceutical compositions comprising a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof, in combination with a non-benzodiazepine ornon-tricyclic agents. Examples of such additional pharmacologicallyactive compounds include, but are limited to: olanzapine, buspirone,hydroxyzine, tomoxetine, and pharmaceutically acceptable salts,solvates, hydrates, clathrates, prodrugs, optically andpharmacologically active stereoisomers, and pharmacologically activemetabolites thereof.

[0090] Chlorpromazine, which is chemically named10-3-dimethylaminopropyl)-2-chlorphenothiazine, is sold under thetradename THORAZINE®. THORAZIN® is indicated, inter alia, for themanagement of manifestations of psychotic disorders. Physician's DeskReference® 3101-3104 (53^(rd) ed., 1999).

[0091] The besylate salt of mesoridazine, which is chemically named10-[2(1-methyl-2-piperidyl)ethyl]-2-methyl-sylfinyl)-phenothiazine, issold under the tradename SERENTIL®. SERENTIL® is indicated in thetreatment of schizophrenia, behavioral problems in mental deficiency andchronic brain syndrome, alcoholism, and psychoneurotic manifestations.Physician's Desk Reference® 764-766 (53^(rd) ed., 1999).

[0092] Perphenazine, which is chemically named4-[3-2-chlorophenothiazin-10-yl)propyl-1-piperazineethanol, is soldunder the tradename TRILAFON®. TRILAFON® is indicated for use in themanagement of the manifestations of psychotic disorders and for thecontrol of severe nausea and vomiting in adults. Physician's DeskReference® 2886-2888 (53^(rd) ed., 1999).

[0093] Trifluoperazine, which is chemically named10-[3-(4-methyl-1-piperazinyl)-propyl]-2-trifluoromethyl)-10-phenothiazine,is sold under the tradename STELAZW®. STELAZWIE® is indicated for themanagement of the manifestations of psychotic disorders and for theshort-term treatment of generalized non-psychotic anxiety. Physician'sDesk Reference® 3092-3094 (53^(rd) ed., 1999).

[0094] Thiothixene, which is chemically namedN,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthene-2-sulfonamide,is sold under the tradename NAVANE®. NAVANE® is indicated in themanagement of manifestations of psychotic disorders. Physician's DeskReference® 2396-2399 (53^(rd) ed., 1999).

[0095] Clozapine, which is chemically named8-chloro-11-(4-methyl-1-piperazinyl)5H-dibenzo[b,e][1,4]diazepine, issold under the tradename CLOZARIL®. CLOZARIL® is indicated for themanagement of severely ill schizophrenic patients who fail to respondadequately to standard antipsychotic drug treatment. Physician's DeskReference® 2004-2009 (53^(rd) ed., 1999).

[0096] Haloperidol, which is chemically named4-[4-(p-chlorophenyl)-4-hydroxypiperidonol-4′-fluorobutyrophenone, issold under the tradename HALDOL®. HALDOL® is indicated for use in themanagement of patients requiring prolonged parenteral antipsychotictherapy (e.g., patients with chronic schizophrenia). Physician's DeskReference® 2190-2192 (53d ed., 1999).

[0097] Loxapine, which is chemically named2-chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1-4]oxaxepine, is soldunder the tradename LOXITANE®. LOXITANE® is indicated for the managementof the manifestations of psychotic disorders. Physician's DeskReference® 3224-3225 (53^(rd) ed., 1999).

[0098] Molindone, which is chemically named3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5H)-onehydrochloride, is sold under the tradename MOBAN®. MOBAN® is indicatedfor the management of the manifestations of psychotic disorders.Physician's Desk Reference® 978-979 (53^(rd) ed., 1999).

[0099] Pimozide, which is chemically named,1-[1-[4,4-bis(4-fluorophenyl)butyl]4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one,is sold under the tradename ORAP®. ORAP® is indicated for thesuppression of motor and phonic tics in patients with Tourette'sDisorder who have failed to respond satisfactorily to standardtreatment. Physician's Desk Reference® 1054-1056 (53^(rd) ed., 1999).

[0100] Risperidone, chemically named3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,is sold under the tradename RISPERDAL®. RISPERDAL® is indicated for themanagement of the manifestations of psychotic disorders. Physician'sDesk Reference® 1432-1436 (53^(rd) ed., 1999).

[0101] The hydrochloride salt of desipramine, which is chemically named5H-Dibenz[b,f]azepine-5-propanamine-10,11-dihydro-N-methyl-monohydrochloride,is sold under the tradename NORPRAMIN®. NORPRAMIN® is indicated for thetreatment of depression. Physician's Desk References 1332-1334 (53^(rd)ed., 1999).

[0102] Olanzapine, which is chemically named2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,is sold under the tradename ZYPREXA®. ZYPREXA® is indicated for themanagement of the manifestations of psychotic disorders. Physician'sDesk Reference® 1641-1645 (53^(rd) ed., 1999).

[0103] The hydrochloride salt of buspirone, which is chemically named8-[4-[4-2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro-[4,5]decane-7,9-dionemonohydrochloride, is sold under the tradename BUSPAR®. BUSPAR® isindicated for the management of anxiety disorders or the short-termrelief of the symptoms of anxiety. Physician's Desk Reference® 823-825(53^(rd) ed., 1999).

[0104] The hydrochloride salt of hydroxyzine, which is chemically named1-(p-chlorobenzhydryl)-4[2-(2-hydroxyethoxy)-ethyl] piperazinedihydrochloride, is sold under the tradename ATARAX®. ATARAX® isindicated for symptomatic relief of anxiety and tension associated withpsychoneurosis and as an adjunct in organic disease states in whichanxiety is manifested. Physician's Desk Reference® 2367-2368 (53^(rd)ed., 1999).

[0105] Disorders that can be treated or prevented using a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof, in combination with anantipsychotic compound, and particularly a tricyclic antipsychoticcompound, include, but are not limited to, affective disorders (e.g.,depression), anxiety, eating disorders, and cerebral function disorders(e.g., schizophrenia) such as those described herein.

[0106] Disorders that can be treated or prevented using a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof, in combination with a compoundselected from the group consisting of lorazepam, tomoxetine, olanzapine,respiradone, buspirone, hydroxyzine, valium, pharmacologically activemetabolites and stereoisomers thereof, and pharmaceutically acceptablesalts, solvates, clathrates thereof include, but are not limited to,anxiety, depression, hypertension, and attention deficit disorders.

[0107] The invention further encompasses methods of using andpharmaceutical compositions comprising a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof, in combination with a 5-HT_(1A) receptorantagonist and/or a β-adrenergic antagonists Examples of 5-HT_(1A)receptor antagonists and β-adrenergic antagonists that can be used inthe methods and compositions of the invention include, but are limitedto: alprenolol; WAY 100135; spiperone; pindolol; (S)-UH-301; penbutolol;propranolol; tertatolol; a compound of the formula I as disclosed inU.S. Pat. No. 5,552,429, which is incorporated herein by reference; andpharmaceutically acceptable salts, solvates, hydrates, clathrates,prodrugs, optically and pharmacologically active stereoisomers, andpharmacologically active metabolites thereof.

[0108] Alprenolol, which is chemically named1-(1-methylethyl)amino-3-[2-(2-propenyl)phenoxy]-2-propanol, isdescribed by U.S. Pat. No. 3,466,325, which is incorporated herein byreference.

[0109] WAY 100135, which is chemically namedN-(t-butyl)-3-[4-(2-methoxphenyl)-piperazin-1-yl]-2-phenylpropanamide,is described by U.S. Pat. No. 4,988,814, which is incorporated herein byreference. See also, Cliffe et al., J. Med. Chem., 36:1509-1510 (1993).

[0110] Spiperone, which is chemically named8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one),is described by U.S. Pat. Nos. 3,155,669 and 3,155,670, both of whichare incorporated herein by reference. See also, Middlmiss et al.,Neurosci. and Biobehav. Rev., 16:75-82 (1992).

[0111] Pindolol, which is chemically named4-(2-hydroxy-3-isopropylaminopropoxy)-indole, is described by U.S. Pat.No. 3,471,515, which is incorporated herein by reference. See also,Dreshfield et al., Neurochem. Res., 21(5):557-562 (1996).

[0112] (S)-UH-301, which is chemically named(S)-5-fluoro-8-hydroxy-2-dipropylaminotetralin), is well known topharmacologists and pharmaceutical chemists. See, e.g. Hillyer et al.,J. Med. Chem., 33:1541-44 (1990) and Moreau et al., Brain Res. Bull.,29:901-04 (1992).

[0113] Penbutolol, which is chemically named(1−(t-butylamino)-2-hydroxy-3-(2-cyclopentyl-phenoxy)propane), is soldunder the tradename LEVATOL®. LEVATOL® is indicated the treatment ofmild to moderate arterial hypertension. Physician 's Desk Reference®2908-2910 (53rd ed., 1999).

[0114] The hydrochloride salt of propranolol, which is chemically named1-isopropylamino-3-(1-naphthalenyloxy)-2-propanol hydrochloride, is soldunder the tradename INDERAL®. INDERAL® is indicated in the management ofhypertension. Physician's Desk Reference® 3307-3309 (53^(rd) ed., 1999).

[0115] Tertatolol, chemically named8-(3-t-butylamino-2-hydroxypropyloxy)-thiochroman, is described by U.S.Pat. No. 3,960,891, which is incorporated herein by reference.

[0116] Disorders that can be treated or prevented using a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof, in combination with a 5-HT_(1A)receptor antagonist include, but are not limited to, depression,obsessive-compulsive disorders, eating disorders, hypertension,migraine, essential tremor, hypertrophic subaortic stenosis andpheochromocytoma. A specific disorder that can be treated or preventedis posttraumatic depression disorder.

[0117] Disorders that can be treated or prevented using a racemic oroptically pure sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, or clathrate thereof, in combination with a β-adrenergicantagonist include, but are not limited to, post myocardial infarctiondepression.

[0118] The invention further encompasses methods of using andpharmaceutical compositions comprising a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof, in combination with a phosphodiesterase inhibitor.Examples of phosphodiesterase inhibitors that can be used incompositions and methods of the invention include, but are not limitedto, those disclosed in U.S. Pat. No. 5,250,534; U.S. Pat. No. 5,719,283;U.S. Pat. No. 6,127,363; WO 94/28902; WO 97/03675; WO 98/06722, all ofwhich are expressly incorporated herein by reference in their entirety.Preferred phosphodiesterase inhibitors are PDE5 and PDE6 inhibitors.Particular phosphodiesterase inhibitors include, but are not limited to,sildenophil (Viagra®), desmethylsildenophil, vinopocetine, milrinone,amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone,rolipran, R020-1724, zaprinast, dipyridamole, and pharmaceuticallyacceptable salts, solvates, hydrates, clathrates, prodrugs, opticallyand pharmacologically active stereoisomers, and pharmacologically activemetabolites thereof.

[0119] Disorders and conditions that can be treated or prevented using asibutramine metabolite, or a pharmaceutically acceptable salt solvate,hydrate, clathrate, or prodrug thereof, in combination with aphosphodiesterase include, but are not limited to, sexual dysfunctionand cerebral function disorders. Others disorders and conditionsinclude, but are not limited to, pain, migraines, osteoarthritis, andrestless leg syndrome.

[0120] While all combinations of racemic and optically pure sibutraminemetabolites and pharmaceutically acceptable salts, solvates, andclathrate thereof, and one or more of the above-describedpharmacologically active compounds can be useful and valuable, certaincombinations are particularly preferred. Examples of preferredcombinations include those wherein a racemic or optically puresibutramine metabolite, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof, is combined with one of the following:alprazolam; mesoridazine; tertatolol; brotizolam; thioridazine;desipramine; chlordiazepoxide; acetophenazine; clonidine; clobazam;fluphenazine; olanzapine; clonazepam; perphenazine; methylphenidate;clorazepate; trifluoperazine; buspirone; demoxepam; chlorprothixene;hydroxyzine; diazepam; thiothixene; tomoxetine; estazolam; clozapine;sildenophil; flumazenil; haloperidol; desmethylsildenophil; flurazepam;loxapine; vinopocetine; halazepam; molindone; milrinone; lorazepam;pimozide; amrinone; midazolam; risperidone; pimobendan; nitrazepam;alprenolol; cilostamide; nordazepam; WAY 100135; enoximone; oxazepam;spiperone; peroximone; prazepam; S(S)-pindolol; vesnarinone; quazepam;R(R)-pindolol; rolipran; temazepam; racemic pindolol; R020-1724;triazolam; (S)-UH-301; zaprinast; or chlorpromazine; penbutolol;dipyridamole.

[0121] Suitable daily dosage ranges of additional pharmacologicallyactive compounds that can be adjunctively administered with sibutraminemetabolite can be readily determined by those skilled in the artfollowing dosages reported in the literature and recommended in thePhyscian's Desk Reference® (54^(th) ed., 2000).

[0122] For example, suitable daily dosage ranges of 5-HT₃ antagonistscan be readily determined by those skilled in the art and will varydepending on factors such as those described herein and the particular5-HT₃ antagonists used. In general, the total daily dose of a 5-HT₃antagonist for the treatment or prevention of a disorder describedherein is from about 0.5 mg to about 500 mg, preferably from about 1 mgto about 350 mg, and more preferably from about 2 mg to about 250 mg perday.

[0123] Similarly, suitable daily dosage ranges of phosphodiesteraseinhibitors can be readily determined by those skilled in the art. Ingeneral, the total daily dose of a phosphodiesterase inhibitor will befrom about 0.5 mg to about 500 mg, from about 1 mg to about 350 mg, orfrom about 2 mg to about 250 mg.

[0124] The therapeutic or prophylactic administration of an activeingredient of the invention (e.g., sibutramine metabolites andadditional pharmacologically active compounds) is preferably initiatedat a lower dose and increased, if necessary, up to the recommended dailydose as either a single dose or as divided doses, depending on theglobal response of the patient. An example of a lower dose ofsibutramine metabolite is from about 0.1 mg to about 1 mg; an example ofa lower dose of 5-HT₃ antagonist is from about 15 mg to about 60 mg. Itis further recommended that patients aged over 65 years should receivedoses of sibutramine metabolite in the range of from about 0.1 mg toabout 10 mg per day depending on global response. It may be necessary touse dosages outside these ranges, which will be readily determinable byone of ordinary skill in the pharmaceutical arts.

[0125] The dosage amounts and frequencies provided above are encompassedby the terms “therapeutically effective,” “prophylactically effective,”and “therapeutically or prophylactically effective” as used herein. Whenused in connection with an amount of a racemic or optically puresibutramine metabolite, these terms further encompass an amount ofracemic or optically pure sibutramine metabolite that induces fewer orless sever adverse effects than are associated with the administrationof racemic sibutramine. Adverse effects associated with racemicsibutramine include, but are not limited to, significant increases insupine and standing heart rate, including tachycardia, increased bloodpressure (hypertension), increased psychomotor activity, dry mouth,dental caries, constipation, hypohidrosis, blurred or blurry vision,tension, mydriasis, seizures, formation of gallstones, renal/hepaticdysfunction, fevers, arthritis, agitation, leg cramps, hypertonia,abnormal thinking, bronchitis, dyspnea, pruritus, amblyopia, menstrualdisorder, ecchymosis/bleeding disorders, interstitial nephritis, andnervousness. See, e.g., Physician's Desk Reference® 1494-1498 (53^(rd)ed., 1999). However, the induction of fewer or less severeadverse-effects is attributable to the administration of a sibutraminemetabolite and the efficacy of which may be less apparent or absent withthe administration of a combination therapy.

[0126] 4.3. Pharmaceutical Compositions

[0127] The invention encompasses pharmaceutical compositions and singleunit dosage forms comprising a sibutramine metabolite, or apharmaceutically acceptable salt, solvate, hydrate, clathrate, orprodrug thereof. Preferred sibutramine metabolites are optically pure.Certain pharmaceutical compositions and unit dosage forms furthercomprise at least one additional pharmacologically active compound.

[0128] The pharmaceutical compositions and dosage forms of thisinvention are particularly useful in the methods herein, and may besuitable for oral, mucosal (e.g., nasal, sublingual, buccal, rectal, andvaginal), parenteral (e.g., intravenous, intramuscular or subcutaneous),or transdermal administration.

[0129] Preferred pharmaceutical compositions and dosage forms comprise asibutramine metabolite, or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, or prodrug thereof in an amount from about 0.1 mg toabout 60 mg, preferably from about 2 mg to about 30 mg, and morepreferably from about 5 mg to about 15 mg. Pharmaceutical compositionsand dosage forms of the invention typically also comprise one or morepharmaceutically acceptable excipients or diluents.

[0130] Single unit dosage forms of the invention are suitable for oral,mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),parenteral (e.g., subcutaneous, intravenous, bolus injection,intramuscular, or intraarterial), or transdermal administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; ointments;cataplasms (poultices); pastes; powders; dressings; creams; plasters;solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;liquid dosage forms suitable for oral or mucosal administration to apatient, including suspensions (e.g. aqueous or non-aqueous liquidsuspensions, oil-in-water emulsions, or a water-in-oil liquidemulsions), solutions, and elixirs; liquid dosage forms suitable forparenteral administration to a patient; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a patient.

[0131] The composition, shape, and type of dosage forms of the inventionwill typically vary depending on their use. For example, a dosage formused in the acute treatment of disorder may contain larger amounts ofone or more of the active ingredients it comprises than a dosage formused in the chronic treatment of the same disorder. Similarly, aparenteral dosage form may contain smaller amounts of one or more of theactive ingredients it comprises than an oral dosage form used to treatthe same disease or disorder. These and other ways in which specificdosage forms encompassed by this invention will vary from one anotherwill be readily apparent to those skilled in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, EastonPa. (1990).

[0132] Typical pharmaceutical compositions and dosage forms comprise oneor more excipients. Suitable excipients are well known to those skilledin the art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms. The suitability of aparticular excipient may also depend on the specific active ingredientsin the dosage form. For example, the decomposition of some activeingredients, such as, desmethylsibutramine and didesmethylsibutramineand its optically active enantiomers in particular, can be acceleratedby some excipients such as lactose, or when exposed to water. Activeingredients that comprise primary or secondary amines are particularlysusceptible to such accelerated decomposition. Consequently, thisinvention encompasses pharmaceutical compositions and dosage forms thatcontain little, if any, lactose or mono- or di-saccharides. As usedherein, the term “lactose-free” means that the amount of lactosepresent, if any, is insufficient to substantially increase thedegradation rate of an active ingredient.

[0133] Lactose-free compositions of the invention can compriseexcipients that are well known in the art and are listed, for example,in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general,lactose-free compositions comprise active ingredients, a binder/filler,and a lubricant in pharmaceutically compatible and pharmaceuticallyacceptable amounts. Preferred lactose-free forms comprise activeingredients, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

[0134] This invention further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising active ingredients, since watercan facilitate the degradation of some compounds. For example, theaddition of water (e.g., 5%) is widely accepted in the pharmaceuticalarts as a means of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

[0135] Anhydrous pharmaceutical compositions and dosage forms of theinvention can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. Pharmaceuticalcompositions and dosage forms that comprise lactose and at least oneactive ingredient that comprises a primary or secondary amine (e.g.,desmethylsibutramine and didesmethylsibutramine) are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

[0136] An anhydrous pharmaceutical composition should be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions are preferably packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g. vials), blister packs, and strip packs.

[0137] The invention further encompasses pharmaceutical compositions anddosage forms that comprise one or more compounds that reduce the rate bywhich an active ingredient will decompose. Such compounds, which arereferred to herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0138] Like the amounts and types of excipients, the amounts andspecific types of active ingredients in a dosage form may differdepending on factors such as, but not limited to, the route by which itis to be administered to patients. However, typical dosage forms of theinvention comprise a racemic or optically pure sibutramine metabolite,or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof in an amount of from about 0.1 mg to about 60 mg,preferably in an amount of from about 2 mg to about 30 mg, and morepreferably in an amount of from about 5 mg to about 15 mg.

[0139] 4.3.1. Oral Dosage Forms

[0140] Pharmaceutical compositions of the invention that are suitablefor oral administration can be presented as discrete dosage forms, suchas, but are not limited to, tablets (e.g., chewable tablets), caplets,capsules, and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

[0141] Typical oral dosage forms of the invention are prepared bycombining the active ingredient(s) in an intimate admixture with atleast one excipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, fillers, and disintegrating agents.

[0142] Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit forms, in which casesolid excipients are employed. If desired, tablets can be coated bystandard aqueous or nonaqueous techniques. Such dosage forms can beprepared by any of the methods of pharmacy. In general, pharmaceuticalcompositions and dosage forms are prepared by uniformly and intimatelyadmixing the active ingredients with liquid carriers, finely dividedsolid carriers, or both, and then shaping the product into the desiredpresentation if necessary.

[0143] For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

[0144] Binders suitable for use in pharmaceutical compositions anddosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0145] Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

[0146] Examples of fillers suitable for use in the pharmaceuticalcompositions and dosage forms disclosed herein include, but are notlimited to, talc, calcium carbonate (e.g., granules or powder),microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, andmixtures thereof. The binder or filler in pharmaceutical compositions ofthe invention is typically present in from about 50 to about 99 weightpercent of the pharmaceutical composition or dosage form.

[0147] Disintegrants are used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Tablets that contain too much disintegrant may disintegratein storage, while those that contain too little may not disintegrate ata desired rate or under the desired conditions. Thus, a sufficientamount of disintegrant that is neither too much nor too little todetrimentally alter the release of the active ingredients should be usedto form solid oral dosage forms of the invention. The amount ofdisintegrant used varies based upon the type of formulation, and isreadily discernible to those of ordinary skill in the art. Typicalpharmaceutical compositions comprise from about 0.5 to about 15 weightpercent of disintegrant, preferably from about 1 to about 5 weightpercent of disintegrant.

[0148] Disintegrants that can be used in pharmaceutical compositions anddosage forms of the invention include, but are not limited to,agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

[0149] Lubricants that can be used in pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

[0150] The magnitude of a prophylactic or therapeutic dose of an activeingredient in the acute or chronic management of a disorder or conditionwill vary with the severity of the disorder or condition to be treatedand the route of administration. The dose, and perhaps the dosefrequency, will also vary according to age, body weight, response, andthe past medical history of the patient. Suitable dosing regimens can bereadily selected by those skilled in the art with due consideration ofsuch factors.

[0151] 4.3.2. Delayed Release Dosage Forms

[0152] Active ingredients of the invention can be administered bycontrolled release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of whichis incorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

[0153] All controlled-release pharmaceutical products have a common goalof improving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

[0154] Most controlled-release formulations are designed to initiallyrelease an amount of drug (active ingredient) that promptly produces thedesired therapeutic effect, and gradually and continually release otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

[0155] 4.3.3. Parenteral Dosage Forms

[0156] Parenteral dosage forms can be administered to patients byvarious routes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

[0157] Suitable vehicles that can be used to provide parenteral dosageforms of the invention are well known to those skilled in the art.Examples include, but are not limited to: Water for Injection USP,aqueous vehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

[0158] Compounds that increase the solubility of one or more of theactive ingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

[0159] 4.3.4. Transdermal, topical, and Mucosal Dosage Forms

[0160] Transdermal, topical, and mucosal dosage forms of the inventioninclude, but are not limited to, ophthalmic solutions, sprays, aerosols,creams, lotions, ointments, gels, solutions, emulsions, suspensions, orother forms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treatingmucosal tissues within the oral cavity can be formulated as mouthwashesor as oral gels. Further, transdermal dosage forms include “reservoirtype” or “matrix type” patches, which can be applied to the skin andworn for a specific period of time to permit the penetration of adesired amount of active ingredients.

[0161] Suitable excipients (e.g., carriers and diluents) and othermaterials that can be used to provide transdermal, topical, and mucosaldosage forms encompassed by this invention are well known to thoseskilled in the pharmaceutical arts, and depend on the particular tissueto which a given pharmaceutical composition or dosage form will beapplied. With that fact in mind, typical excipients include, but are notlimited to, water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

[0162] Depending on the specific tissue to be treated, additionalcomponents may be used prior to, in conjunction with, or subsequent totreatment with active ingredients of the invention. For example,penetration enhancers can be used to assist in delivering the activeingredients to the tissue. Suitable penetration enhancers include, butare not limited to: acetone; various alcohols such as ethanol, oleyl,and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide;dimethyl acetamide; dimethyl formamide; polyethylene glycol;pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone,Polyvidone); urea; and various water-soluble or insoluble sugar esterssuch as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[0163] The pH of a pharmaceutical composition or dosage form, or of thetissue to which the pharmaceutical composition or dosage form isapplied, may also be adjusted to improve delivery of one or more activeingredients. Similarly, the polarity of a solvent carrier, its ionicstrength, or tonicity can be adjusted to improve delivery. Compoundssuch as stearates can also be added to pharmaceutical compositions ordosage forms to advantageously alter the hydrophilicity or lipophilicityof one or more active ingredients so as to improve delivery. In thisregard, stearates can serve as a lipid vehicle for the formulation, asan emulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

[0164] 4.3.5. Kits

[0165] Typically, active ingredients of the invention are preferably notadministered to a patient at the same time or by the same route ofadministration. This invention therefore encompasses kits which, whenused by the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a patient.

[0166] A typical kit of the invention comprises a unit dosage form of asibutramine metabolite, or a pharmaceutically acceptable prodrug, salt,solvate, hydrate, or clathrate thereof, and a unit dosage form of anadditional pharmacologically active compound. Examples of additionalpharmacologically active compounds are disclosed herein.

[0167] Kits of the invention can further comprise devices that are usedto administer the active ingredients. Examples of such devices include,but are not limited to, syringes, drip bags, patches, and inhalers.

[0168] Kits of the invention can further comprise pharmaceuticallyacceptable vehicles that can be used to administer one or more activeingredients. For example, if an active ingredient is provided in a solidform that must be reconstituted for parenteral administration, the kitcan comprise a sealed container of a suitable vehicle in which theactive ingredient can be dissolved to form a particulate-free sterilesolution that is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:Water for Injection USP; aqueous vehicles such as, but not limited to,Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles such as, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehiclessuch as, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0169] The invention is further defined by reference to the followingexamples. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, can be practiced withoutdeparting from the scope of this invention.

5. EXAMPLES

[0170] Examples 1-2 describe the preparation of racemic and opticallypure sibutramine.

[0171] Examples 3-8 describe the preparation of racemic and opticallypure forms of desmethylsibutramine (DMS). In each of these examples, theenantiomeric purity of DMS was determined using a Chirobiotic Vanalytical column (10 mm, 4.6 mm×25 mm) with 20 mm ammonium acetate/IPA(65:35) as the mobile phase. The UV detector was set to a wavelength of222 nm.

[0172] Examples 9-12 describe the preparation of racemic and opticallypure forms of didesmethylsibutramine (DDMS). In each of these examples,the enantiomeric purity of DDMS was determined using an ULTRON ES-OVManalytical column (150 mm×4.6 mm) with 0.01 M KH₂PO₄/MeOH (70:30) as themobile phase. The UV detector was set to a wavelength of 200 nm.

[0173] Examples 13-14 describe methods of determining binding affinitiesof the compounds of the invention and binding affinities measured usingthose methods.

[0174] Finally, Example 15 describes oral formulations comprisingcompounds of the invention.

5.1. Example 1 Synthesis of Sibutramine

[0175] Synthesis of 1-(4-Chlorophenyl)cyclobutanecarbonitrile

[0176] To a suspension of NaH (17.6 g 60%, washed with hexane) indimethylsulfoxide (150 mL) at room temperature with mechanical stirringwas added over a one hour period a mixture of chlobenzylnitrile (30.3 g)and 1,3-dibromopropaine (22.3 mL, 44.5 g). The reaction mixture wasstirred for an additional 1 hour, and isopropyl alcohol (10 mL) wasadded slowly to quench excess NaH. Water (150 mL) was added. Thereaction mixture was extracted with t-butyl methyl ether (MTBE) (2×200mL), and the combined extracts were washed with water (3×200 mL), brine,and dried over MgSO₄. The solvent was removed in a rotoevaporator, andthe final product was purified by distillation to give the titlecompound (22 g, 56%) as pale yellow oil, bp 110-120° C./1.0 mm Hg. Theproduct was characterized by ¹H NMR.

[0177] Synthesis of 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine

[0178] A solution of isobutylmagnesium bromide (2M, 108 mL) in diethylether (Aldrich) was concentrated to remove most of the ether. Theresidue was dissolved in toluene (150 mL), followed by addition of thenitrile made above (22 g). The reaction mixture was heated to 105° C.for 17 hours. The reaction mixture was cooled to room temperature, andadded to a slurry of NaBH₄ in isopropyl alcohol (450 mL). The reactionmixture was heated under reflux for 6 hours, cooled to room temperatureand concentrated. The residue was diluted with water (350 mL), andextracted with ethyl acetate (3×200 mL). The combined extracts werewashed with water (100 mL), and dried (MgSO₄), and concentrated to give24.2 g crude product (83%).

[0179] Synthesis of Sibutramine Free Base

[0180] 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (21.6 g) wasadded to formic acid (27 mL) and aqueous formaldehyde (46 mL). Thereaction mixture was heated to 8595° C. for 18 hours and was cooled toroom temperature. 30% NaOH was added until the mixture was basic(pH>11). The solution was extracted with chloroform (3×200 mL) and theextracts were combined and washed with water and brine and concentratedto give 15 g product.

[0181] Sibutramine HCl

[0182] Sibutramine free base (2.25 g) was dissolved in MTBE (20 mL) andthat solution was added to 20 mL 1M HCl in diethyl ether. The reactionmixture was stirred for 30 minutes, and the solid was collected byfiltration to give 1.73 g after drying. The product was characterized by¹H NMR.

[0183] Resolution of Sibutramine

[0184] 12.3 g racemic sibutramine was dissolved in ethyl acetate (85mL), and a solution of 21.7 g L-dibenzyltartaric acid (“L-DBTA”) inethyl acetate (85 mL) was added thereto. The reaction mixture was heatedto reflux and cooled to room temperature. The white precipitate wascollected (ee of salt is ca 85%). The solid was then suspended in 220 mLethyl acetate and heated at reflux for 30 minutes. The solid wascollected to give >95% ee. The salt was further crystallized inisopropyl alcohol (450 mL) to give 11.3 g of salt with >99.3% ee.(S)-Sibutramine L-DBTA (yield 76%). Free base was obtained by treatmentof the salt with saturated aqueous NaHCO₃ and extracted with chloroform.The (S)-sibutramine HCl salt was obtained with treatment of the freebase with HCl/Et₂O as described above. Optical rotation of the HCl saltwas [α]=3.15 (c=0.9, H₂O), ¹H NMR ¹³C (CD₃OD), and M⁺=279. Theresolution mother liquor was treated with NaOH to give the partiallyenriched (R)-sibutramine and was then treated with D-DBTA as describedabove to give (R)-sibutramine-D-DBTA salt with >99.3% ee. Thesibutramine enantiomers were characterized by ¹H and ¹³C NMR: M⁺=279.The material was also characterized by HPLC and Chiral HPLC.

5.2. Example 2 Sibutramine from its Metabolites

[0185] Racemic and optically pure sibutramine can also be prepared bymethylation of desmethylsibutramine or dimethylation ofdidesmethylsibutramine under suitable reaction conditions. An example ofthis method is shown in Scheme 1.

5.3. Example 3 Desmethylsibutramine from Sibutramine

[0186] (S)-Sibutramine (1.25 g) was dissolved in toluene (90 mL) anddiethylazodicarboxylate (“DEAD”) was added (0.8 g, 10.1 eq). Thereaction mixture was heated at 50° C. for 6 hours, and 0.8 g DEAD wasadded. The reaction was heated at 50° C. for another 6 hours, cooled toroom temperature and the toluene was removed under vacuum. The residuewas suspend in 45 mL of ethanol and 45 mL of saturated aqueous NH₄Cl.The reaction mixture was heated under reflux for 3 hours. The reactionmixture was cooled to room temperature and concentrated to removeethanol. Aqueous NaHCO₃ was added until the concentrate was basic. Thebasic concentrate was extracted with dichloromethane, (3×50 mL). Theextracts were combined, dried with sodium sulfate, filtered andconcentrated to give a crude product. Flash column chromatography (SiO₂)(ethyl acetate/TEA 99:1) gave 0.43 g product. It was characterized by ¹Hand ¹³C NMR, M⁺=266, and optical rotation [α]=−10.6, c=3.3, (CHCl₃.) Theother enantiomer and racemate were prepared similarly and the isomer wascharacterized as the (S)-isomer.

[0187] Synthesis of Desmethylsibutramine Hydrochloride Isomers

[0188] To a solution of (S)-desmethylsibutramine (0.78 g) in ethylacetate (5 mL) at 0° C. was added HCl/diethyl ether (1 M, 5 mL). Thereaction mixture was stirred for 1 hour and the solid was collected byfiltration. The solid was then dried to give 0.68 g white solid. Theproduct was characterized by ¹H and 1³C NMR (DMSO-d₆), and a chemicalpurity of >99% was determined by HPLC. [α]=−5° (c=0.5, H₂O). Theracemate and the other enantiomer were prepared and characterized in thesame way.

5.4. Example 4 (R/S)-Desmethylsibutramine

[0189] Another method of preparing racemic desmethylsibutramine((R/S)-DMS) is shown in Scheme 2 and described in detail below:

[0190] Preparation of 1-(4-Chlorophenyl)-1-cyclobutyl Carboxaldehyde

[0191] Following Scheme 2, diisobutylaluminum hydride (DIBAL-H) (87 mL,1M in THF, 87.0 mmol) was added to a solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (CCBC; 10 g, 52.1 mmol) maintained at −20° C.The resulting mixture was stirred for 4-5 hours at 0° C. and then pouredinto a 10% aqueous citric acid solution and diluted with 200 mL MTBE.The mixture was stirred at room temperature for 3-4 hours. The aqueouslayer was washed with MTBE (1×50 mL) and the combined organic layerswere dried over MgSO₄ and concentrated to give 9 g (89%) of theabove-captioned aldehyde as an oil. ¹H NMR (CDCl₃) d 9.52 (s, 1H),7.35-7.06 (m, 4H), 2.77-2.68 (m, 2H), 2.43-2.32 9 m, 2H), 2.06-1.89 (m,2H). ¹³C NMR d 198.9, 139.4, 132.9, 128.9, 127.8, 57.1, 28.3, 15.8.

[0192] Preparation of 1-(4-chlorophenyl)-1-cyclobutyl N-methylcarbamine

[0193] A mixture of 1-(4-chlorophenyl)-1-cyclobutyl carboxaldehyde (3 g,15.4 mmol) and methyl amine (12 mL, 40% aqueous w/w, 154 mmol) wasstirred at room temperature for 18-40 hours. The reaction mixture wasextracted with MTBE (2×50 mL). The combined organic layers were driedover K₂CO₃ and concentrated to give 2.5 g (78%) of the above-captionedimine as an oil. ¹H NMR (CDCl₃) d 7.65 (m, 1H), 7.33-7.11 (m, 4H), 3.34(s, 3H), 2.69-2.44 (m, 2H), 2.44-2.34 (m, 2H), 2.09-1.84 (m, 2H), ¹³CNMR d 168.0, 144.0, 131.8, 128.4, 127.4, 50.6, 30.6, 15.8.

[0194] Preparation of1-(4-chlorophenyl)-N-methyl-2-(2-methylpropyl)-cyclobutanamethamine

[0195] To a solution of 1-(4-chlorophenyl)-1-cyclobutylN-methylcarbaimine (0.5 g, 2.4 mmol) cooled to 0° C. was added BF₃.OEt₂(0.34 g, 2.4 mmol). The mixture was stirred for 1 hour and then cooledto −78° C. At this temperature, isobutyl magnesium bromide (2.5 mL, 2Min ether, 5 mmol) was added to form a mixture which was stirred at −78°C. for 2 hours and then warmed to room temperature and stirredovernight. The reaction was quenched with saturated NaHCO₃ solution (10mL) and diluted with MTBE (15 mL). The organic layer was dried overMgSO₄, concentrated, and purified by silicagel chromatography (elutingwith 1% NEt₃ in ethyl acetate) to give 380 mg of the above captionedamine as an oil. ¹H NMR (CDCl₃) d 7.35-7.19 (m, 4H), 2.65-2.74 (m, 1H),2.57 (s, 3H), 2.20-2.56 (m, 5H), 1.60-2.00 (m, 3H), 1.20-1.00 (m, 2H),0.95-0.90 (m, 6H), 0.67-0.60 (m, 1H). ¹³C NMR 144.7, 131.3, 129.1,127.4, 65.5, 51.7, 41.4, 37.4, 33.7, 32.3, 25.4, 24.0, 22.0, 16.3.

5.5. Example 5 (R/S)-Desmethylsibutramine.HCl

[0196] A method of preparing the hydrochloride salt of racemicdesmethylsibutramine ((R/S)-DMS.HCl) is shown in Scheme 3:

[0197] Following Scheme 3, toluene (150 mL) and a solution of CCBC (50.0g, 261 mmol) in toluene (45 mL) were added to a solution of isobutylmagnesium bromide in THF (392 mL, 1M in THF, 392 mmol). The resultingmixture was distilled until the internal temperature reached 105-110° C.and as then refluxed at this temperature for 2-4 hours. The reactionmixture was then cooled to 0° C. and quenched with methanol (295 mL).NaBH₄ (11 g, 339 mmol) was added portion-wise over 15 minutes to thereaction mixture at 0° C. After stirring for 15 minutes, the reactionmixture was transferred into a 2N aqueous HCl solution (365 mL). Theorganic phase was distilled until the internal temperature reached 105°C., and was then allowed to cool to room temperature. Formic acid (24 g,522 mmol) was then added to the reaction mixture, which was then heatedto reflux (92-96° C.) for 6-8 hours after which time the reactionmixture was distilled until the internal temperature reached 108° C. Themixture was then cooled to 10° C. and BH₃.THF (653 mL, 1.0 M, 653 mmol)was added. The resulting mixture was heated to reflux (69° C.) for 15hours. The mixture was then cooled to 5° C., combined with methanol (105mL), and refluxed again for 45 minutes. The reaction mixture wasdistilled until the internal temperature reached 116° C., and thenallowed to cool to 25° C. Hydrochloric acid in MTBE (373 g, 18 wt % ofHCl, 1840 mmol) was then added to the mixture to provide a white slurrywhich was refluxed for 1 hour and then filtered to give 62.3 g (79.0%)of (R/S)-DMS.HCl. NMR (CDCl₃): ¹H (d), 0.85-1.1 (m, 6H), 1.24-1.5 (b,2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (b,1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). ¹³C (d): 15.5, 21.4, 23.5, 24.7,31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.6. Example 6 (R)-Desmethylsibutramine.HCl

[0198] A method of preparing the hydrochloride salt of(R)-desmethylsibutramine ((R)-DMS.HCl) is shown in Scheme 4 anddescribed in detail below:

[0199] Formation of (R)-Mandelate Salt of (R)-DMS

[0200] (R/S)-Desmethylsibutramine HCl ((R/S)-DMS.HCl) (60 g) was addedto ethyl acetate (300 mL) and the resulting mixture was cooled to 0° C.Aqueous NaOH (1.5 N, 300 mL) was then added to the reaction mixture,which was then stirred for 30 minutes. The organic phase was separated,washed with water (150 mL), and concentrated. (R)-Mandelic acid (30.3g), ethyl acetate (510 mL total), and heptane (204 mL) were then addedto the concentrated organic phase. The resulting mixture was then heatedto reflux for 1 hour, after which time it was cooled to 20-23° C.Filtration of the resulting slurry yielded 36.4 g (43.8%) of(R)-desmethylsibutramine-(R)-mandelate ((R)-DMS.(R)-MA; 95.5% ee).

[0201] Enrichment of (R)-DMS.(R)-MA

[0202] A mixture of (R)-DMS.(R)-MA (30 g, 0.072 mol), ethyl acetate (230mL), and heptane (230 mL) was heated to reflux for 1 hour. After coolingto 20-23° C., the product was filtered and dried to give 29.6 g (98%) of(R)-DMS.(R)-MA (99.9% ee).

[0203] Formation of HCl Salt of (R)-DMS

[0204] A mixture of (R)-DMS.(R)-MA (50 g, 0.12 mol), NaOH (100 ml, 3.0N), and toluene (500 mL) was stirred for 30 minutes. The organic phasewas washed with water (200 mL), concentrated to about 300 mL, and cooledto room temperature. HCl/MTBE (100 mL, 14%, 0.34 mol) was then slowlyadded to the mixture to form (R)-DMS.HCl. After stirring for 30 minutes,the slurry was filtered and the resulting wet cake was washed two timeswith MTBE and dried to give 34.5 g (95.5%) of (R)-DMS.HCl (99.9% cc;99.9% chemically pure by NMR). NMR (CDCl₃): ¹H (d), 0.85-1.1 (m, 6H),1.24-1.5 (b, 2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H),3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). ¹³C (d): 15.5, 21.4,23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0,141.6.

5.7. Example 7 (S)-Desmethylsibutramine-HCl

[0205] A method of preparing the hydrochloride salt of(S)-desmethylsibutramine (S)-DMS.HCl) is shown in Scheme 5 and describedin detail below:

[0206] Formation of (S)-Mandelate Salt of (S)-DMS

[0207] Following Scheme 5, a mixture of (R/S)-DMS.HCl (5.0 g), NaOH(1.5N, 20 mL) and ethyl acetate (50 mL) was stirred for 30 minutes. Theorganic phase was washed with water (20 mL) and concentrated to givedesmethylsibutramine free base (4.2 g, 96%).

[0208] Desmethylsibutramine free base (1.1 g, 4.1 mmol) was combinedwith (S)-mandelic acid (0.62 g, 4.1 mmol), ethyl acetate (11 mL), andheptane (4.4 mL). The resulting mixture was heated to reflux for 30minutes and cooled to 20-23° C. Filtration of the resulting slurry gave0.76 g of (S)-desmethylsibutramine-(S)-mandelate salt ((S)-DMS.(S)-MA)(96% ee).

[0209] Enrichment of (S)-DMS.(S)-MA

[0210] A mixture of (S)-Desmethylsibutramine.(S)-mandelate (0.76 g),ethyl acetate (5 mL), and heptane (5 mL) was heated to reflux for 1hour. After cooling to 20-23° C., the product was filtered and dried togive 0.72 g (95%) of(S)-DMS.(S)-MA (99.9% cc).

[0211] Recovery of (S)-Mandelate Salt of (S)-DMS from Mother Liquor of(S-DMS.(R)-MA

[0212] A solution of (S)-DMS.(R)-MA in ethyl acetate-heptane (67% eemother liquor) was charged with NaOH (3N, 400 mL) and the reactionmixture was stirred for 30 minutes. The organic phase was washed withwater and concentrated. The resulting residue (130 g, 0.49 mol and 67%ee) was charged with (S)-mandelic acid (28.5 g, 0.49 mol), ethyl acetate(1400 mL), and heptane (580 mL). The mixture was heated to reflux for 1hour and then slowly cooled to room temperature. The resulting slurrywas filtered and dried to give 147 g (86% based on (S)-isomer) of(S)-DMS.(S)-MA (99.9% ee).

[0213] Formation of HCl Salt of (S)-DMS

[0214] (S)-Desmethylsibutramine-(S)-mandelate (20 g, 0.048 mol) wasadded to a mixture of NaOH (60 ml, 3.0 N) and toluene (200 mL). Themixture was stirred for 30 minutes and the organic phase was then washedwith water (100 mL), concentrated to about 100 mL, and cooled to roomtemperature. Hydrochloric acid in MTBE (40 mL, 14%, 0.13 mol) was thenadded slowly to the mixture to form (S)-DMS.HCl. After stirring for 30minutes, the slurry was filtered and the resulting wet cake was washedtwo times with MTBE and dried to give 14 g (96.7%) of (S)-DMS.(L)-MA(99.9% ee; 99.9% chemical purity). NMR (CDCl₃): ¹H (d), 0.84-1.1 (m,6H), 1.25-1.5 (b, 2H), 1.65-2.15 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m,2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). ¹³C (d): 15.5,21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4,133.0, 141.6.

5.8. Example 8 Desmethylsibutramine from Didesmethylsibutramine

[0215] Racemic and optically pure didesmethylsibutramine can also beprepared by methylation of didesmethylsibutramine under suitablereaction conditions. An example of this method is shown in Scheme 6.

[0216] 5.9. Example 9

(R/S)-Didesmetrylsibutramine

[0217] A preferred method of preparing racemic didesmethylsibutraminefree base ((R/S)-DDMS) is shown in Scheme 7 and described in detailbelow.

[0218] Following Scheme 7, a 1 L three-necked round bottom flask wascharged with isobutyl magnesium bromide (200 mL, 2.0 M in diethyl ether)and toluene (159 mL) and the resulting mixture was distilled to removemost of the ether. After the mixture was cooled to 20° C., CCBC (50.0 g)in toluene (45 mL) was added, and resulting mixture was refluxed for 2-4hours. The reaction mixture was then cooled to 0° C. and methanol (300mL) was added to it, followed slowly by NaBH₄ (11 g). The resultingmixture was then stirred at about 0-10° C. for 15 minutes. The reactionmixture was then added slowly to an aqueous HCl solution (365 mL, 2N)kept at 0° C., and the resulting mixture was warmed to room temperaturewith continual stirring. After separation of the organic phase, theaqueous phase was washed with toluene (200 mL). The combined organicphases were washed with water (200 mL) and concentrated to give(R/S)-DDMS (55 g, 85%). NMR (CDCl₃): ¹H (d), 0.6-0.8 (m, 1H), 0.8-1.0(m, (6H), 1.1-1.3 (m, 1H), 1.6-2.6 (m, 7H), 3.0-3.3 (m, 1H), 7.0-7.6 (m,4H). ¹³C (d): 15.4, 21.5, 24.3, 24.7, 31.5, 31.9, 41.1, 50.73, 56.3,127.7, 129, 131.6, 144.3.

5.10. Example 10 (R/S)-didesmethylsibutramine-(D)-tartrate

[0219] A preferred method of preparing the (D)-tartrate salt of racemicdidesmethylsibutramine ((R/S)-DDMS.(D)-TA) is shown below in Scheme 8.It should be noted that the (L)-tartrate salt of racemicdidesmethylsibutramine ((R/S)-DDMS.(L)-TA) can be prepared in ananalogous manner.

[0220] Following Scheme 8, a mixture of racemic didesmethylsibutramine(15.3 g) and toluene (160 mL) was heated to 70-80° C. and (D)-tartaricacid (9.1 g) in water (20 mL) and acetone (10 mL) was added slowly. Theresulting mixture was refluxed for 30 minutes, after which the water andacetone were removed by distillation. The resulting mixture was cooledto room temperature to provide a slurry which was then filtered. Theresulting wet cake was washed two times with MTBE (20 mL×2) and dried toyield (R/S)-DDMS.(D)-TA (22.5 g, 98%). NMR (DMSO): ¹H (d), 0.6-0.92 (m,6H), 0.92-1.1 (m, 1H), 1.1-1.3 (m, 1H), 1.5-1.8 (m, 2H), 1.8-2.1 (m, 1H,2.1-2.4 (m, 3H), 2.4-2.6 (m, 1H), 3.4-3.6 (m, 1H), 3.9-4.2 (s, 2H),6.4-7.2 (b, 6H, OH, COOH, and NH₂), 7.3-7.6 (m, 4H). ¹³C (d): 15.5, 2.1,23.3, 3.7, 31.5, 31.8, 37.7, 39.7, 54.5, 72.1, 128, 129.7, 131.3, 149.2,174.6.

5.11. Example 11 (R)-didemethylsibutramine-(D)-tartrate

[0221] Resolution from Didesmethylsibutramine Free Base

[0222] A method of isolating the (D)-tartrate salt of(R)-didesmethylsibutramine ((R)-DDMS.(D)-TA) from racemicdidesmethylsibutramine free base is shown in Scheme 9A and described indetail below:

[0223] Following Scheme 9A, a mixture of (R/S)-didesmethylsibutramine(20.3 g), acetone/water/methanol (350 mL, 1:0.13:0.7, v:v:v), and(D)-tartaric acid (12.1 g) were added to a 500 mL three-necked roundbottom. The reaction mixture was heated to reflux for 30 minutes andthen cooled to 45° C. The reaction mixture was then seeded with(R)-DDMS.(D)-TA (10 mg; 99.6% ee) and stirred at 40-45° C. for 30minutes. The mixture was then cooled to room temperature and stirred for1 hour. The resulting slurry was then filtered and the wet cake waswashed with cold acetone/water and dried to give 10.3 g (33%) of(R)-DDMS.(D)-TA (90% ee).

[0224] Resolution from (R/S)-Didesmethylsibutramine-(D)-tartrate

[0225] A method of isolating the (D)-tartrate salt of(R)-didesmethylsibutramine ((R)-DDMS.(D)-TA) from the (D)-tartrate saltof racemic didesmethylsibutramine is shown in Scheme 9B and described indetail below.

[0226] Following Scheme 9B, a mixture of(R/S)-didesmethylsibutramine.(D)-TA (5.0 g) in acetone (50 mL), water(6.7 mL), and methanol (3.3 mL) was refluxed for 30 minutes. The mixturewas then cooled to room temperature and the resulting slurry wasfiltered to provide a wet cake which was then washed with cold acetoneand dried to give (R)-DDMS.(D)-TA (1.4 g, 28%; 92% ee).

[0227] Enrichment of (D)-Tartrate Salt of (R)-DDMS

[0228] A mixture of (R)-DDMS.(D)-TA (25 g, 92% ee) andacetonitrile/water/ethanol (300 mL:65 mL:30 mL) was refluxed for 1 hour.The mixture was then cooled to room temperature to provide a slurrywhich was filtered and dried to give (R)-DDMS.(D)-TA (18 g, 71.3%; 99.7%ee; and 99.91% chemical purity). NMR (DMSO-d₆): ¹H (d), 0.7-0.9 (m, 6H),0.9-1.05 (t, 1H), 1.1-1.24 (b, 1H), 1.5-1.8 (b, 2H), 1.8-2.02 (b, 1H),2.1-2.4 (3, 3H), 2.4-2.6 (b, 1H), 3.5 (m, 1H), 4.0 (s, 2H), 7.1-7.6 (m,4H, with 6H from NH₂, OH and COOH). ¹³C (d): 15.4, 21.5, 22.0, 22.2,32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0, 175.5.

5.12. Example 12 (S)-didesmethylsibutramine-(L)-tartrate

[0229] A method of isolating the (L)-tartrate salt of(S)-didesmethylsibutramine ((S)-DDMS.(L)-TA) from racemicdidesmethylsibutramine free base is shown in Scheme 10 and described indetail below:

[0230] Formation of (L)-Tartrate Salt of (S)-DDMS

[0231] (R/S) Didesmethylsibutramine (20.5 g), acetone/water/methanol(350 mL, 1:0.13:0.7, v:v:v) and (L)-tartaric acid (12.2 g) were added toa 500 mL three-necked round bottom flask. The mixture was heated toreflux for 30 minutes and then cooled to 45° C. The reaction mixture wasthen seeded with (S)-DDMS.(L)-TA (10 mg and 99.7% ee) and stirred at40-45° C. for 30 minutes. The mixture was cooled to room temperature andstirred for 1 hour. The resulting slurry was filtered to provide a wetcake, which was washed with cold acetone/water and dried to give 10.8 g(33.4%) of (S)-DDMS.(L)-TA (89.7% ee).

[0232] Preparation of (L)-Tartrate Salt of (S)-DDMS from Mother Liquorof (R)-DDMS.(D)-TA

[0233] A solution of DDMS tartrate in acetone/water/methanol (motherliquor of (R)-DDMS.(D)-TA) was concentrated to remove acetone andmethanol. The residue was treated with aqueous NaOH (3N, 150 mL) andextracted with ethyl acetate. The organic phase was washed with water(100 mL) and concentrated to give didesmethylsibutramine free base (45g, 0.18 mol and 36% ee of (S)-isomer). The free amine was charged with(L)-tartaric acid (53.6 g, 0.35 mol), acetone (600 mL), water (80 mL),and methanol (40 mL). The mixture was heated to reflux for 1 hour andthen cooled to room temperature. The resulting slurry was filtered toprovide a wet cake, which was then washed with cold acetone/water twotimes to give 26.7 g (56% based on (S)-didesmethylsibutramine) of(S)-DDMS.(L)-TA (96% ee).

[0234] Enrichment of (S)-DDMS.(L)-TA

[0235] A mixture of (S)-DDMS.(L)-TA (26.7 g) in acetonitrile/water (475mL; 1:0.2, v:v) was refluxed for 1 hour and then cooled to roomtemperature. The resulting slurry was filtered and dried to give 17.4 g(65%) of (S)-DDMS.(L)-TA (99.9% ee; 99.94% chemical purity). NMR(DMSO-d6): ¹H (d), 0.7-0.9 (m, 6H), 0.9-1.05 (m, 1H), 1.1-1.3 (b, 1H),1.52-1.8 (b, 2H), 1.84-2.05 (b, 1H), 2.15-2.4 (b, 3H), 2.4-2.6 (b, 1H),3.65-3.58 (m, 1H), 4.0 (s, 2H), 6.7-7.3 (b, 6H from NH₂, OH and COOH)7.1-7.6 (m, 4H). ¹³C (d): 15.4, 21.5, 22.0, 22.2, 32.0, 32.2, 38.4,49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0, 175.5.

5.13. Example 13 Determination of Potency an Specificity

[0236] A pharmacologic study is conducted to determine the relativepotency, comparative efficacy, binding affinity, and toxicity of theracemic mixture of sibutramine, its enantiomers, the metabolites ofsibutramine, and their enantiomers. The profile of relative specificityof monoamine reuptake inhibition is determined from the compounds'inhibition of norepinephrine (NE) reuptake in brain tissue with that ofthe inhibition of dopamine (DA) and serotonin 5-HT) reuptake.

[0237] High-affinity uptake of the ³H-radiomonoamines is studied insynaptosomal preparations prepared from rat corpus striatum (forinhibition of DA reuptake) and cerebral cortex (for 5HT and NE) usingmethods published by Kula et al., Life Sciences 34(26): 2567-2575, 1984,and Baldessarini et al., Life Sciences 39:1765-1777, 1986. Tissues arefreshly dissected on ice and weighed. Following homogenization by hand(14 strokes in 10-35 vols of ice-cold isotonic 0.32M sucrose, containingnialamide, 34 μM) in a Teflon-on-glass homogenizer, the tissue iscentrifuged for ten minutes at 900×g; the supernatant “solution” thatresults contains synaptosomes that are used without further treatment.Each assay tube contains 50 mL of the cerebral homogenate,radiolabelled-³H-monoamine, and the test compound (e.g., the puresibutramine enantiomers, the racemate, and appropriate standards) in afreshly prepared physiologic buffer solution with a final volume of 0.5mL. Tissues are preincubated for 15 minutes at 37° C. before the assay.Tubes are held on ice until the start of incubation, which is initiatedby adding ³H-amine to provide a final concentration of 0.1 μM. Tubes areincubated at 37° C for 10 minutes with ³H-DA (26 Ci/mmol) and for 20minutes with ³H-5HT (about 20 Ci/mmol) and ³H-NE (about 20 Ci/mmol). Thespecific activity of the radiomonoamine will vary with availablematerial and is not critical. The reaction is terminated by immersion inice and dilution with 3 mL of ice cold isotonic saline solutioncontaining 20 mM TRIS buffer (pH 7.0). These solutions are filteredthrough cellulose ester microfilters, followed by washing with two 3 mLvolumes of the same buffer. The filter is then counted for³H-radioactivity in 3.5 mL of Polyfluor at about 50% efficiency fortritium. Blanks (either incubated at 0° C. or incubated with specific,known uptake inhibitors of DA [GRB-12909, 10 μM], 5HT-[zimelidine 10μM], or of NE [desipramine 10 μM]) are usually indistinguishable fromassays performed without tissue and average 2-3% of total CPM.

[0238] Comparison of the amounts of ³H-radioactivity retained on thefilters provides an indication of the relative abilities of the pureenantiomers and racemic mixture of sibutramine (and of known DA, 5-HT,and NE reuptake inhibitors) to block the reuptake of these monoamines inthose tissues. This information is useful in gauging the relativepotency and efficacy of compounds of the invention (e.g., dopaminereuptake inhibitors, such as a racemic or optically pure sibutraminemetabolite, and 5-HT₃ antagonists).

[0239] The acute toxicities of the compounds of the invention aredetermined in studies in which rats are administered progressivelyhigher doses (mg/kg) of the pure isomers or racemate. That lethal dosewhich, when administered orally, causes death of 50% of the testanimals, is reported as the LD₅₀. Comparison of LD₅₀ values for theenantiomers and racemate provides a measure of the relative toxicity ofthe compositions.

5.14. Example 14 Binding Affinities

[0240] The binding affinities of racemic and optically pure sibutramine((R/S)-, (R)-, and (S)-sibutramine), desmethylsibutramine ((R/S)-, (R)-,and (S)-desMe), and didesmethylsibutramine ((RIS)-, (R)-, and(S)-didesMe) were determined at the nonselective muscarinic receptor andthe serotonin (5-HT) uptake site from rat cerebral cortex, the humanrecombinant norepinephrine (NE) uptake site, and the β₃-receptor fromrat adipose tissue. Compounds were tested initially at 10 μm induplicate, and if 250% inhibition of specific binding was observed, theywere tested further at 10 different concentrations in duplicate in orderto obtain full competition curves. IC₅₀ values (concentration requiredto inhibit 50% specific binding) were then determined by nonlinearregression analysis of the curves and tabulated below. Binding IC₅₀Values (nM) Muscarinic NE 5-HT 5-HT Selectivity Compound Receptor UptakeUptake (NE/5-HT) (R/S)-Sibutramine 2,650 350 2,800 1,200 (R)-Sibutramine4,010 110 2,100 650 (S)-Sibutramine 3,020 2,500 4,900 1,500 (R/S)-desMe1,170 10 21 19 (R)-desMe — 4 44 12 (S)-desMe 654 870 9,200 180(R/S)-didesMe — 16 63/14 39/26 (R)-didesMe — 13 140 8.9 (S)-didesMe —6.2 4,300 12 Atropine 0.31 — — — GBR 1909 — — — 5.6/2.6 Imipramine — —145/32 — Protriptyline — 3.6/0.9 — — Zimelidine — — 129 —

[0241] None of the compounds showed more than 15% inhibition of bindingat the β₃-receptor, and affinity for the muscarinic site was weakcompared to atropine. Further, binding to the NE and 5-HT uptake siteswas orders of magnitude less than that of the standards.

[0242] The above data, which was generated as described above in Example13, shows that (R)-desmethylsibutramine and (R)-didesmethylsibutramineare potent inhibitors of NE uptake and 5-HT uptake, but have negligibleactivity at muscarinic receptors.

5.15. Example 15 Oral Formulation

[0243] Hard gelatin capsule dosage forms that are lactose-freecomprising sibutramine metabolites can be prepared using the followingingredients: Component 5 mg capsule 10 mg capsule 20 mg capsule Racemicor optically 5.0 10.0 20.0 pure sibutramine metabolite Microcrystalline90.0 90.0 90.0 Cellulose Pre-gelatinized 100.3 97.8 82.8 StarchCroscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2 Stearate

[0244] The racemic or optically pure sibutramine metabolite is sievedand blended with the excipients listed. The mixture is filled intosuitably sized two-piece hard gelatin capsules using suitable machineryand methods well known in the art. See, e.g., Remington's PharmaceuticalSciences, 16th or 18th Editions, each incorporated herein in itsentirety by reference. Other doses can be prepared by altering the fillweight and, if necessary, changing the capsule size to suit. Any of thestable, non-lactose hard gelatin capsule formulations above can beformed.

[0245] Compressed tablet dosage forms of sibutramine metabolites can beprepared using the following ingredients: Component 5 mg capsule 10 mgcapsule 20 mg capsule Racemic or optically 5.0 10.0 20.0 puresibutramine metabolite Microcrystalline 90.0 90.0 90.0 CellulosePre-gelatinized 100.3 97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0Magnesium 0.2 0.2 0.2 Stearate

[0246] The racemic or optically pure sibutramine metabolite is sievedthrough a suitable sieve and blended with the non-lactose excipientsunit a uniform blend is formed. The dry blend is screened and blendedwith the magnesium stearate. The resulting powder blend is thencompressed into tablets of desired shape and size. Tablets of otherstrengths can be prepared by altering the ratio of the active ingredientto the excipient(s) or modifying the table weight.

[0247] The embodiments of the invention described above are intended tobe merely exemplary and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the invention andare encompassed by the following claims.

What is claimed is:
 1. A method of treating or preventing sexualdysfunction which comprises administering to a patient in need of suchtreatment or prevention therapeutically or prophylactically effectiveamounts of a sibutramine metabolite, or a pharmaceutically acceptablesalt, solvate, hydrate, clathrate, or prodrug thereof, and aphosphodiesterase inhibitor.
 2. The method of claim 1 wherein thesibutramine metabolite is optically pure.
 3. The method of claim 2wherein the sibutramine metabolite is (R)-desmethylsibutramine,(S)-desmethylsibutramine, (R)-didesmethylsibutramine, or(S)-didesmethylsibutramine.
 4. The method of claim 1 wherein thephosphodiesterase inhibitor is a PDE5 or PDE6 inhibitor.
 5. The methodof claim 4 wherein the phosphodiesterase inhibitor is sildenophil,desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan,cilostamide, enoximone, peroximone, vesnarinone, rolipram, R020-1724,zaprinast, dipyridamole, or a pharmaceutically acceptable salt, solvate,hydrate, clathrate, prodrug, optically and pharmacologically activestereoisomer, or a pharmacologically active metabolite thereof.
 6. Themethod of claim 1 wherein the amount of sibutramine metaboliteadministered is from about 0.1 mg to about 60 mg/day.
 7. The method ofclaim 6 wherein the amount of sibutramine metabolite administered isfrom about 2 mg to about 30 mg/day.
 8. The method of claim 7 wherein theamount of sibutramine metabolite administered is from about 5 mg toabout 15 mg/day.
 9. The method of claim 1 wherein the sibutraminemetabolite and/or the phosphodiesterase inhibitor is administeredtransdermally or mucosally.
 10. The method of claim 1 wherein thepatient is male.
 11. The method of claim 10 wherein the sexualdysfunction is erectile dysfunction.
 12. The method of claim 1 whereinthe patient is female.
 13. A method of treating or preventing a cerebralfunction disorder which comprises administering to a patient in need ofsuch treatment or prevention therapeutically or prophylacticallyeffective amounts of a sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof, and aphosphodiesterase inhibitor.
 14. The method of claim 13 wherein thecerebral function disorder is senile dementia, Alzheimer's typedementia, memory loss, amnesia/amnestic syndrome, disturbance ofconsciousness, coma, lowering of attention, speech disorders,Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkineticsyndrome, or schizophrenia.
 15. The method of claim 13 wherein thesibutramine metabolite is optically pure.
 16. The method of claim 15wherein the sibutramine metabolite is (R)-desmethylsibutramine,(S)-desmethylsibutramine, (R)-didesmethylsibutramine, or(S)-didesmethylsibutramine.
 17. The method of claim 13 wherein thephosphodiesterase inhibitor is a PDE5 or PDE6 inhibitor.
 18. The methodof claim 17 wherein the phosphodiesterase inhibitor is sildenophil,desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan,cilostamide, enoximone, peroximone, vesnarinone, rolipram, R020-1724,zaprinast, dipyridamole, or a pharmaceutically acceptable salt, solvate,hydrate clathrate, prodrug, optically and pharmacologically activestereoisomer, or a pharmacologically active metabolite thereof.
 19. Themethod of claim 13 wherein the amount of sibutramine metaboliteadministered is from about 0.1 mg to about 60 mg/day.
 20. The method ofclaim 19 wherein the amount of sibutramine metabolite administered isfrom about 2 mg to about 30 mg/day.
 21. The method of claim 20 whereinthe amount of sibutramine metabolite administered is from about 5 mg toabout 15 mg/day.
 22. A method of treating or preventing restless legsyndrome which comprises administering to a patient in need of suchtreatment or prevention a therapeutically or prophylactically effectiveamount of a racemic or optically pure sibutramine metabolite, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.
 23. The method of claim 22 wherein the sibutramine metaboliteis optically pure.
 24. The method of claim 23 wherein the sibutraminemetabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine,(R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.
 25. Themethod of claim 22 which further comprises the administration ofpergolide, carbidopa, levodopa, oxycodone, carbamazepine, or gabapentin,or a pharmaceutically acceptable salt, solvate, hydrate, clathrate,prodrug, optically and pharmacologically active stereoisomer, orpharmacologically active metabolite thereof.
 26. A pharmaceuticalcomposition comprising a sibutramine metabolite, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof, and aphosphodiesterase inhibitor.
 27. The pharmaceutical composition of claim26 wherein the sibutramine metabolite is optically pure.
 28. Thepharmaceutical composition of claim 27 wherein the sibutraminemetabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine,(R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.
 29. Thepharmaceutical composition of claim 28 wherein the phosphodiesteraseinhibitor is sildenophil, desmethylsildenophil, vinopocetine, milrinone,amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone,rolipram, R020-1724, zaprinast, dipyridamole, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, prodrug, optically andpharmacologically active stereoisomer, or a pharmacologically activemetabolite thereof.
 30. The pharmaceutical composition of claim 26wherein the sibutramine metabolite is in an amount of from about 0.1 mgto about 60 mg.
 31. The pharmaceutical composition of claim 30 whereinthe sibutramine metabolite is in an amount of from about 2 mg to about30 mg.
 32. The pharmaceutical composition of claim 31 wherein thesibutramine metabolite is in an amount of from about 5 mg to about 15mg.
 33. The pharmaceutical composition of claim 26 wherein thephosphodiesterase inhibitor is in an amount of from about 0.5 mg toabout 500 mg.
 34. The pharmaceutical composition of claim 33 wherein thephosphodiesterase inhibitor is in an amount of from about 1 mg to about350 mg.
 35. The pharmaceutical composition of claim 34 wherein thephosphodiesterase inhibitor is in an amount of from about 2 mg to about250 mg.
 36. The pharmaceutical composition of claim 26 wherein thepharmaceutical composition is adapted for oral, mucosal, rectal,parenteral, transdermal, or subcutaneous administration.
 37. Thepharmaceutical composition of claim 36 wherein the pharmaceuticalcomposition is adapted for oral, mucosal, or transdermal administration.38. A lactose-free pharmaceutical composition which comprises asibutramine metabolite, or a pharmaceutically acceptable salt, solvate,or clathrate thereof, a phosphodiesterase inhibitor, and apharmaceutically acceptable excipient.
 39. The pharmaceuticalcomposition of claim 38 wherein the excipient is croscarmellose sodium,microcrystalline cellulose, pre-gelatinized starch, or magnesiumstearate.
 40. The pharmaceutical composition of claim 39 wherein saidpharmaceutical composition is substantially free of mono- ordi-saccharides.